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. Author manuscript; available in PMC: 2013 Jul 16.
Published in final edited form as: Chem Res Toxicol. 2012 May 10;25(7):1316–1383. doi: 10.1021/tx300132k

Contributions of Human Enzymes in Carcinogen Metabolism

Slobodan Rendic 1,*, F Peter Guengerich 2
PMCID: PMC3398241  NIHMSID: NIHMS373973  PMID: 22531028

Abstract

Considerable support exists for roles of metabolism in modulating the carcinogenic properties of chemicals. In particular, many of these compounds are procarcinogens that require activation to electrophilic forms to exert genotoxic effects. We systematically analyzed the existing literature on metabolism of carcinogens by human enzymes, which has been developed largely in the past 25 years. The metabolism and especially bioactivation of carcinogens are dominated by cytochrome P450 enzymes (66% of bioactivations). Within this group, six P450s—1A1, 1A2, 1B1, 2A6, 2E1, and 3A4—accounted for 77% of the P450 activation reactions. The roles of these P450s can be compared with those estimated for drug metabolism and should be considered in issues involving enzyme induction, chemoprevention, molecular epidemiology, inter-individual variations, and risk assessment.

INTRODUCTION

Knowledge that chemicals can cause cancer goes back to at least 1761 with the report by Hill1 that the use of tobacco snuff was related to oral cancer in humans. More than 100 years ago, Rehn2 reported an association of bladder cancer with occupations in the so-called aniline dye factories. Experimental studies in animals showed that chemicals cause cancer, beginning with reports on coal tar in rabbits by Yamagiwa.3 Classic studies with the polycyclic aromatic hydrocarbon benzo[a]pyrene followed.4 Fieser5 and others had suggested that metabolism (of carcinogens1) plays a role in cancer, and extensive animal studies by James and Elizabeth Miller6-8 validated the concept (Figure 1). Incorporation of the capability for metabolism led to the success of the bacterial Ames test9 for mutagenicity and testing for carcinogenic potential.

Figure 1.

Figure 1

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General paradigm of metabolism of chemical carcinogens.

The roles of individual enzymes in carcinogen metabolism has been studied extensively, and roles of many human P450s in carcinogen activation have been characterized.10 Much of this work was first done in medium-throughput screens, e.g. bacterial genotoxicity, and then extended with more detailed studies of reaction products and DNA adducts.10-13 Studies with P450s led the way but similar approaches have been used with other enzymes known to have roles in the metabolism of xenobiotic chemicals.14,15 Research in this area has been important in several applied disciplines and approaches. These include molecular epidemiology, which is an attempt to relate risk from carcinogens to the enzymes present in an individual.16-18 Another area of interest is chemoprevention, where a major strategy involves either inhibiting enzymes that activate carcinogens or inducing enzymes that inactive them.19,20

Several efforts have been made to delineate the levels of expression of individual enzymes, especially P450s, in humans.21 Another approach is to analyze the fractions of the enzymes involved in reactions. Such analyses have been reported for drugs, for all “xenobiotic-metabolizing enzymes”22,23 and for P450s.22-25 The analyses are rather consistent with each other and generally accepted, both with marketed drugs and new chemical entities (drug candidates). Of particular note are the findings that i) ~75% of enzymatic reaction with drugs are catalyzed by P450s,23 ii) ~90% of the P450 reactions can be accounted for by a set of five P450s: 1A2, 2C9, 2C19, 2D6, and 3A4,23-25 and iii) the largest fraction of the P450 reactions are catalyzed by P450 3A enzymes, particularly P450 3A4.23-25

To our knowledge, there has not been a similar effort to categorize all of the the human enzymes involved in the metabolism of carcinogens. We thought that this would be a useful exercise in the light of continuing scientific interest in chemical carcinogenesis, cancer chemoprevention, and molecular epidemiology of cancer. We report our analysis of the literature in parts—general chemicals (environmental/industrial),Footnote 1 drugs, and natural/physiological compounds—as well as an overall analysis of all literature carcinogens for which information about metabolism is available. The results show a dominant role for P450s, especially the three Family 1 P450 enzymes (1A1, 1A2, 1B1) and P450s 2A6, 2E1, and 3A4 (Figure 2). The aldo-keto reductase (AKR) enzymes are also highly represented.26

Figure 2.

Figure 2

Figure 2

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Enzyme contributions to activation of carcinogens (from Table 1). A: Fractions of activation reactions attributed to groups of enzymes. The analysis is based on 713 reactions. B: Fractions of P450 activation reactions attributed to individual human P450 enzymes (from a total of 473 reactions considered). See text for discussion.

ASSIGNMENTS OF ROLES OF ENZYMES

Most of the literature on the roles of human enzymes in carcinogen metabolism has been developed in the last 25 years, e.g. a review by one of us in 198827 had only a very limited discussion of this aspect. The present literature analysis is a continuation of the work done by one of us (S. Rendic) on literature searches on the metabolism of drugs and other chemicals catalyzed by human P450s, for more than 15 years ending in February 2012. Extensive key-word literature searches were done using the PubMed database, accessing the MEDLINE database of references and abstracts. In the latter stages, the existing literature on metabolism of carcinogens and the original papers was systematically analyzed, extracting those data contributing in a “significant way” to the activation and/or detoxication of general chemicals, drugs, and physiological compounds. (This is a qualitative evaluation, and the reader is referred to a more comprehensive list in Supporting Information Table S1.)

The results are presented in several tables (Tables 1-4), including activation reactions with all chemicals (Table 1) (exclusive of “weak” reactions), followed by the activation of physiological/natural compounds (Table 2) and drugs (Table 3). Detoxication reactions are presented in Table 4. For convenience, PMID numbers of references are included in the tables to facilitate searches and retrievals. In considering the results for all types of metabolism, it is clear that P450s are dominant. The three activation tables (Tables 1-3) contain only data for what are deemed “significant activation”. All activation data (potent and weak) are presented as a single table in the Supporting Information (Table S1).

Table 1. Data on individual enzymes and chemicals, but not including weak bioactivation (see Supporting Information for inclusion of weak activation data).

Note: the term “diol” is used in stead of “dihydrodiol” for convenience with the PAHs.

enzyme category subcategory compound reaction remarks references PubMed ID
AKR1A1 chemical PAH, metabolite (±)-benzo[a]pyrene-7,8-
dihydrodiol		 oxidation, o-quinone
formation, preferential for
(−)-7R,8R-oxidation		 activation 26, 28-33 16411658,
11306097,
9973208,
11535067,
15720144,
17295519,
18788756
AKR1A1 chemical PAH, metabolite 12-methylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation		 activation 28 11306097
AKR1A1 chemical PAH, metabolite 5-methylchrysene-1,2-diol oxidation, o-quinone
formation (medium Km,
high activity, high
efficiency)		 activation 28, 30, 34 11306097,
11535067,
16946553
AKR1A1 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
form.		 activation 28,30 11306097,
11535067
AKR1A1 chemical PAH, metabolite 7-methylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation, preferential for
(−)3S,4S-oxidation		 activation 28, 30 11306097,
11535067
AKR1A1 chemical PAH, metabolite benz[a]anthracene-3,4-diol oxidation, o-quinone
formation, preferential for
(−)3R,4R-oxidation		 activation 28, 30 11306097,
11535067
AKR1A1 chemical PAH, metabolite chrysene-1,2-diol oxidation, o-quinone
formation		 activation 28 11306097
AKR1B1 chemical PAH (+)-benz[a]anthracene-
3S,4S-diol		 oxidation, o-quinoneform, stereospecific for
(+)-7S-,8S 		activation 33 18788756
AKR1B1 chemical PAH, metabolite (+)-benzo[a]pyrene-7S,8S-
diol		 oxidation, o-quinone
formation, stereospecific
for (+)-7S-,8S 		activation 33 18788756
AKR1B1 chemical PAH, metabolite (+)-S,S-benzo[g]chrysene-
11,12-diol		 oxidation, o-quinone
formation, stereospecific
for (+)-7S-,8S 		activation 33 18788756
AKR1B10 chemical PAH, metabolite (−)-R,R- and (+)-S,S-
benzo[g]chrysene-11,12-diol		 oxidation, o-quinone
formation		 activation 33 18788756
AKR1B10 chemical PAH, metabolite (+)-benz[a]anthracene-3S,4S-
diol		 oxidation, o-quinone
formation, stereospecific
for (+)-7S-,8S 		activation 33 18788756
AKR1B10 chemical PAH, metabolite (+)-benzo[a]pyrene-7S,8S-
diol		 oxidation, o-quinone
formation, stereospecific
for (+)-7S-,8S 		activation 33 18788756
AKR1B10 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation		 activation 33 18788756
AKR1C1 chemical PAH, metabolite (+,−)- and (−)-
benzo[a]pyrene-7,8-diol		 oxidation, o-quinone
formation		 activation 29, 33, 35,
36 		9973208,
18788756,
11978787,
11060293
AKR1C1 chemical PAH, metabolite 5-methylchrysene-7,8-diol oxidation, o-quinone
formation		 activation 35, 36 11978787,
11060293
AKR1C1 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation, minor enzyme		 activation 35, 36 11978787,
11060293
AKR1C1 chemical PAH, metabolite 7-methylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation, minor enzyme		 activation 35 11978787
AKR1C1 chemical PAH, metabolite benz[a]anthracene-3,4-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C1 chemical aromatic hydrocarbon benzene diol oxidation, o-quinone
formation		 activation 36, 37 11060293,
15026176
AKR1C1 chemical PAH, metabolite benzo[g]chrysene-11,12-diol oxidation, o-quinone
formation		 activation 35, 36 11978787,
11060293
AKR1C1 chemical PAH, metabolite naphthalene 1,2-diol oxidation, o-quinone
formation, major enzyme		 activation 35, 36 11978787,
11060293
AKR1C2 chemical PAH, metabolite (±)- and (−)-benzo[a]pyrene-
7,8-diol		 oxidation, o-quinone
formation		 activation 29, 33, 35 9973208,
18788756,
11978787
AKR1C2 chemical PAH, metabolite 5-methylchrysene-7,8-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C2 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation		 activation 35 11978787
AKR1C2 chemical PAH, metabolite 7-methylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation		 activation 35 11978787
AKR1C2 chemical PAH, metabolite benz[a]anthracene-3,4-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C2 chemical PAH, metabolite benzene diol oxidation, o-quinone
formation		 activation 37 15026176
AKR1C2 chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol		 oxidation, o-quinone
form.		 activation 35 11978787
AKR1C2 chemical PAH, metabolite benzo[g]chrysene-11,12-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C2 chemical PAH, metabolite chrysene-1,2-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C2 chemical PAH, metabolite naphthalene 1,2-diol oxidation, o-quinone
formation, major enzyme		 activation 35 11978787
AKR1C3 chemical PAH, metabolite (+,−)- and (−)-
benzo[a]pyrene-7,8-
dihydrodiol		 oxidation, o-quinone
formation		 activation 29, 33, 35 9973208,
18788756,
11978787
AKR1C3 chemical PAH, metabolite 5-methylchrysene-7,8-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C3 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation		 activation 35 11978787
AKR1C3 chemical PAH, metabolite 7-methylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation		 activation 35 11978787
AKR1C3 chemical PAH, metabolite benz[a]anthracene-3,4-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C3 chemical aromatic hydrocarbon,
metabolite		 benzene diol oxidation, o-quinone
formation		 activation 37 15026176
AKR1C3 chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol		 oxidation, o-quinone
formation		 activation 35 11978787
AKR1C3 chemical PAH, metabolite benzo[g]chrysene-11,12-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C3 chemical PAH, metabolite chrysene-1,2-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C3 chemical PAH, metabolite naphthalene 1,2-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C4 chemical PAH, metabolite (±)- and (−)-benzo[a]pyrene-
7,8-diol		 oxidation, o-quinone
formation		 activation 29, 35 9973208,
11978787
AKR1C4 chemical PAH, metabolite (±)-benzo[a]pyrene-7,8-diol oxidation, o-quinone
formation		 activation 33 18788756
AKR1C4 chemical PAH, metabolite 5-methylchrysene-7,8-diol oxidation, o-quinone
formation, major enzyme		 activation 35 11978787
AKR1C4 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation, major enzyme		 activation 35 11978787
AKR1C4 chemical PAH, metabolite 7-methylbenz[a]anthracene-
3,4-diol		 oxidation, o-quinone
formation		 activation 35 11978787
AKR1C4 chemical PAH, metabolite benz[a]anthracene-3,4-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C4 chemical aromatic hydrocarbon,
metabolite		 benzene diol oxidation, o-quinone
formation		 activation 37 15026176
AKR1C4 chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol		 oxidation, o-quinone
formation		 activation 35 11978787
AKR1C4 chemical PAH, metabolite benzo[g]chrysene-11,12-diol oxidation, o-quinone
formation, major enzyme		 activation 35 11978787
AKR1C4 chemical PAH, metabolite chrysene-1,2-diol oxidation, o-quinone
formation		 activation 35 11978787
AKR1C4 chemical PAH, metabolite naphthalene 1,2-diol oxidation, o-quinone
formation		 activation 35 11978787
COX-1 chemical PAH, metabolite (±)- and (+)-benzo[a]pyrene-
7,8-diol		 oxidation activation 38 11159734
COX-1 chemical heterocyclic amine 2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (MeIQx)		 oxidation activation 38 11159734
COX-1 chemical arylamine 4,4′-methylene bis(2-
chloroaniline) (MOCA)		 oxidation potent
activation		 38 11159734
COX-1 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl oxidation activation 38 11159734
COX-1 chemical arylamine benzidine oxidation activation 38 11159734
COX-1 drug pyrido-carbazole;
antineoplastic,
alkaloid,
Apocyanaceae plant
compound,
topoisomerase II
inhibitor, DNA
binding		 ellipticine oxidation activation 39, 40 16936898,
21753906
COX-2 chemical PAH, metabolite (±)- and (+)-benzo[a]pyrene-
7,8-diol		 oxidation activation 38 11159734
COX-2 chemical heterocyclic amine 2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (MeIQx)		 oxidation activation 38 11159734
COX-2 chemical arylamine 4,4′-methylene bis(2-
chloroaniline) (MOCA)		 oxidation potent
activation		 38 11159734
COX-2 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl oxidation activation 38 11159734
COX-2 chemical arylamine benzidine oxidation activation 38 11159734
COX-2 drug pyrido-carbazole;
antineoplastic,
alkaloid,
Apocyanaceae plant
compound,
topoisomerase II
inhibitor, and DNA
binding		 ellipticine oxidation activation 39, 40 16936898,
21753906
CYP1A1 chemical PAH, metabolite (±)-, (−)-, and (+)-
benzo[a]pyrene-7,8-diol		 trans-(anti)-7,8-
dihydroxy-9,10-epoxy-
7,8,9,10-tetrahydroformation
(trans-diol
epoxide formation);
oxidation		 potent
activation		 13, 31, 32,
34, 41-52 		2509067,
8674051,
7955101,
11502724,
11238186,
8043197,
7581497,
11952781,
15720144,
10426814,
8293790,
16946553,
16885195,
17295519,
17525473,
21028851
CYP1A1 chemical nitroarene 1,8-dinitropyrene nitroreduction potent
activation		 53 11113705
CYP1A1 chemical arylamine, metabolite
of 1-nitropyrene		 1-aminopyrene oxidation activation 54 11525925
CYP1A1 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-
(diallylamino)-5-
methoxyphenyl]-5-amino-7-
bromo-4-chloro-2H-
benzotriazole
(PBTA-8)		 oxidation activation 55 18562244
CYP1A1 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-
(diethylamino)-5-
methoxyphenyl]-5-amino-7-
bromo-4-chloro-2H-
benzotriazole (PBTA-7)		 oxidation activation 55 18562244
CYP1A1 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-amino-
5-methoxyphenyl]-5-amino-
7-bromo-4-chloro-2H-
benzotriazole (PBTA-4)		 oxidation activation 55 18562244
CYP1A1 chemical benzotriazole 2-[2-(acetylamino)-4-amino-
5-methoxyphenyl]-5-amino-
7-bromo-4-chloro-2H-
benzotriazole (PBTA-4)		 oxidation activation 56 21786339
CYP1A1 chemical arylamine, metabolite 2-acetylaminofluorene (2-
AAF)		 N-hydroxylation,
oxidation		 activation 41, 43, 57 8674051,
11502724,
15279838
CYP1A1 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 N-hydroxylation,
oxidation		 activation 41, 43, 57-
61 		8674051,
11502724,
15279838,
9111224,
9855011,
21081470,
1377247
CYP1A1 chemical heterocyclic amine 2-amino-3,4-
dimethylimidazo[4,5-
f]quinoline (MeIQ)		 N-hydroxylation,
oxidation		 potent
activation		 41, 43, 49,
56, 62, 63 		8674051,
11502724,
10426814,
21786339,
11473383,
8200084
CYP1A1 chemical heterocyclic amine 2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (MeIQx)		 N-hydroxylation,
oxidation		 activation 41, 43, 49,
58, 62-64 		8674051,
11502724,
10426814,
9111224,
11473383,
8200084,
17627018
CYP1A1 chemical heterocyclic amine 2-amino-3-
methylimidazo[4,5-
f]quinoline (IQ)		 N-hydroxylation,
oxidation		 potent
activation		 41, 43, 49,
58, 61, 65 		8674051,
11502724,
10426814,
9111224,
11377247,
9918136
CYP1A1 chemical heterocyclic amine 2-amino-6-
methyldipyrido[1,2-a:3′,2′-d]-
imidazole (Glu-P-1)		 N-hydroxylation,
oxidation		 activation 41, 43, 61 8674051,
11502724,
11377247
CYP1A1 chemical arylamine 2-aminoanthracene N-hydroxylation,
oxidation (high activity)		 potent
activation		 41, 43, 61,
66 		8674051,
11502724,
11377247,
9685642
CYP1A1 chemical arylamine 2-aminofluorene N-hydroxylation,
oxidation		 activation 41, 43, 49,
61 		8674051,
11502724,
10426814,
11377247
CYP1A1 chemical nitroarene 2-nitronaphthalene nitroreduction activation 67 10521697
CYP1A1 chemical nitroarene 2-nitropyrene 2-aminopyrene formation
(nitroreduction)		 activation 41 8674051
CYP1A1 chemical nitrosamine 3-(n-nitrosomethylamino) propiona
ldehyde		 oxidation activation 68 15725615
CYP1A1 chemical nitrosamine 3-(N-
nitrosomethylamino) propioni
trile		 oxidation (at high
concentrations)		 activation 68, 69 15725615,
16720019
CYP1A1 chemical nitroarene 3,6-dinitrobenzo[e]pyrene nitroreduction activation 70 19393727
CYP1A1 chemical heterocyclic amine 3-Amino-1,4-dimethyl-5H-
pyrido[4,3-b]indole (Trp-P-1)		 N-hydroxylation,
oxidation		 potent
activation		 41, 43, 49,
61, 66, 71 		8674051,
11502724,
10426814,
11377247,
9685642,
9721189
CYP1A1 chemical heterocyclic amine 3-amino-1-methyl-5H-
pyrido[4,3-b]indole (Trp-P-2)		 N-hydroxylation,
oxidation		 activation 41, 43, 49,
61-63, 66 		8674051,
11502724,
10426814,
11377247,
11473383,
8200084,
9685642
CYP1A1 chemical arylamine, metabolite 3-aminobenzanthrone N-hydroxylation activation 72, 73 15885895,
16601755
CYP1A1 chemical azoaromatic amine 3-methoxy-4-
aminoazobenzene (3-MeO-
AAB)		 oxidation potent
activation		 41, 43, 49,
66 		8674051,
11502724,
10426814,
9685642
CYP1A1 chemical PAH 3-methylcholanthrene (3MC) oxidation activation 74 11360624
CYP1A1 chemical PAH, metabolite 3-methylcholanthrene-11,12-
diol, 3MC-11,12-diol		 oxidation activation 43 11502724
CYP1A1 natural
compound		 indole, alkylating,
pulmonary toxin; in
higher concentrations
in mammalian
digestive tract and coal
tar		 3-methylindole, skatole epoxidation (3-
methyloxindole
formation);
dehydrogenation
(desaturation, 3-
methyleneindolenine
formation), low Km,
medium activity, high
efficiency		 activation 75-78 8558432,
11408359,
12563100,
20795680
CYP1A1 chemical nitroarene 3-nitrobenzanthrone nitroreduction activation 73, 79, 80 16601755,
12740904,
12782579
CYP1A1 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl N-hydroxylation,
oxidation		 activation 41, 58, 66 8674051,
9111224,
9685642
CYP1A1 chemical PAH, metabolite 5,6-dimethylchrysene-1,2-
diol		 oxidation activation 34, 43, 49,
81 		16946553,
11502724,
10426814,
14720319
CYP1A1 chemical PAH 5-methylchrysene 1,2-dihydrodiol formation
(medium Km, high
activity, high efficiency),
oxidation		 activation 43, 81-83 11502724,
14720319,
8542586,
18992797
CYP1A1 chemical PAH, metabolite 5-methylchrysene-1,2-diol oxidation potent
activation		 34, 41, 43,
49, 81, 83 		16946553,
8674051,
11502724,
10426814,
14720319,
18992797
CYP1A1 chemical arylamine 6-aminochrysene oxidation (high activity) potent
activation		 41, 43, 66 8674051,
11502724,
9685642
CYP1A1 chemical arylamine, metabolite 6-aminochrysene-1,2-diol diol epoxide formation,
oxidation		 activation 41, 84, 85 8674051,
8118930,
8330339
CYP1A1 chemical PAH 6-methylchrysene 1,2-dihydrodiol formation activation 82 8542586
CYP1A1 chemical nitroarene 6-nitrochrysene oxidation activation 43 11502724
CYP1A1 chemical PAH 7,12-
dimethylbenz[a]anthracene		 oxidation (low Km, high
activity and efficiency)		 potent
activation		 43, 49, 81,
86, 87 		11502724,
10426814,
14720319,
12584184,
20507880
CYP1A1 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 3,4-dihydrodiol-1,2-
epoxide formation
(medium Km, high
activity, high efficiency),
oxidation		 potent
activation		 34, 43, 49,
66, 74, 81 		16946553,
11502724,
10426814,
9685642,
11360624,
14720319
CYP1A1 chemical N-heterocyclic
aromatic hydrocarbon		 7H-dibenzo[c,g]carbazole oxidation potent
activation		 88-91 10984687,
12034315,
15534862,
21809388
CYP1A1 chemical PAH, aza-aromatic 7-methylbenz[c]acridine 3,4-dihydrodiol formation activation 92 7866988
CYP1A1 chemical PAH, aza-aromatic 7-methylbenz[c]acridine oxidation potent
activation		 92 7866988
CYP1A1 chemical PAH, metabolite 9-hydroxybenzo[a]pyrene oxidation activation 43 11502724
CYP1A1 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 epoxidation 8,9-,
oxidation		 activation 41, 57, 61,
93, 94 		8674051,
15279838,
11377247,
7923587,
8200084
CYP1A1 chemical heterocyclic amine aminomethylphenylnorharma
n		 N-hydroxylation activation 95 17067997
CYP1A1 natural
compound		 phenanthroic acid
derivative;
nephrotoxin, found in
the Aristolochiaceae
family of plants		 aristolochic acid I nitroreduction potent
activation		 96-99 11511187,
15386410,
16125300,
22086975
CYP1A1 natural
compound		 phenanthroic acid
derivative;
nephrotoxin, found in
the Aristolochiaceae
family of plants		 aristolochic acid II nitroreduction activation 96-99 11511187,
15386410,
16125300,
22086975
CYP1A1 chemical PAH benz[a]anthracene oxidation activation 43, 81, 100 11502724,
14720319
CYP1A1 chemical PAH, metabolite benz[a]anthracene-1,2-diol oxidation activation 34, 43, 74,
101 		16946553,
11502724,
11360624,
11377097
CYP1A1 chemical PAH, metabolite benz[a]anthracene-3,4-diol oxidation activation 34, 43, 81 16946553,
11502724,
14720319
CYP1A1 chemical PAH, metabolite benz[a]anthracene-5,6-diol oxidation activation 34, 43 16946553,
11502724
CYP1A1 chemical diphenylmethanol,
metabolite		 benzhydrol oxidation activation 102 12160905
CYP1A1 chemical PAH benzo[a]perylene oxidation activation 103 10613181
CYP1A1 chemical PAH benzo[a]pyrene trans-7,8-dihydroxy-9,10-
epoxy-7,8,9,10-
tetrahydro- formation
(low activity, medium
activity, or high activity,
high efficiency); 1,6-,3,6-,
6,12-dione (quinone
formation, low activity);
oxidation		 activation 41, 43, 50-
52, 57, 81,
93, 94,
104-108 		8674051,
11502724,
16885195,
17525473,
21028851,
15279838
14720319,
7923587,
8200084,
9806168,
11513247,
8037457,
1486866,
19501186
CYP1A1 chemical PAH, metabolite benzo[b]fluoroanthene-9,10-
diol		 oxidation potent
activation		 34, 41, 43,
49, 66, 81 		16946553,
8674051,
11502724,
10426814,
9685642,
14720319
CYP1A1 chemical PAH benzo[c]phenanthrene dihydrodiol 3,4-, 1,2-
epoxide formation (major
enzyme); oxidation		 activation 109 11409939
CYP1A1 chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol		 dihydrodiol 3,4-, 1,2-
epoxide formation;
oxidation		 activation 43, 49 11502724,
10426814
CYP1A1 chemical PAH, metabolite benzo[g]chrysene-11,12-diol oxidation activation 34, 43, 49,
81 		16946553,
11502724,
10426814,
14720319
CYP1A1 chemical aromatic ketone,
diphenyl ketone		 benzophenone oxidation activation 102 12160905
CYP1A1 chemical PAH, metabolite chrysene-1,2-diol oxidation potent
activation		 43, 49, 81 11502724,
10426814,
14720319
CYP1A1 chemical PAH cyclopenta[c,d]pyrene oxidation activation 110 7923587
CYP1A1 Drug imidazole; anticancer,
alkylating		 dacarbazine N-demethylation (major
extrahepatic enzyme)		 activation 111 10473105
CYP1A1 chemical PAH, metabolite, aza-
aromatic		 dibenz[a,h]acridine 10,11-diol formation potent
activation		 112 15144224
CYP1A1 chemical PAH dibenz[a,h]anthracene oxidation activation 43 11502724
CYP1A1 chemical PAH, aza-aromatic dibenz[a,j]acridine 3,4-dihydrodiol formation activation 92 7866988
CYP1A1 chemical PAH dibenzo[a,e]fluoranthene oxidation activation 103 10613181
CYP1A1 chemical PAH dibenzo[a,e]pyrene oxidation activation 103 10613181
CYP1A1 chemical PAH dibenzo[a,f]fluoranthene oxidation activation 103 10613181
CYP1A1 chemical PAH dibenzo[a,h]pyrene oxidation activation 103 10613181
CYP1A1 chemical PAH dibenzo[a,k]fluoranthene oxidation activation 103 10613181
CYP1A1 chemical PAH dibenzo[a,l]pyrene (−)-syn- and (−)-anti-
11,12-dihydrodiol-13,14-
epoxide formation
(medium Km, high
activity, high efficiency);
oxidation		 potent
activation		 43, 81, 103,
113-119		 11502724,
14720319,
10613181,
9625737,
10207125,
10493514,
10506751,
8968059,
16581046,
17509623
CYP1A1 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 11,12-dihydrodiol-13,14-
epoxide formation
(medium Km, high
activity, high efficiency);
oxidation		 potent
activation		 34, 43, 49,
71, 81,
113-115,
118-120 		16946553,
11502724,
10426814,
9721189,
14720319,
9625737,
10207125,
10493514,
16581046,
17509623,
16485905
CYP1A1 chemical PAH dibenzo[b,k]fluoranthene oxidation activation 103 10613181
CYP1A1 physiologi
-cal
compound		 estrogen 17β−estradiol C2-hydroxylation (major
reaction, medium Km,
high activity, high
efficiency), major
metabolite and major
extrahepatic enzyme; C4-
hydroxylation (minor
reaction, medium Km,
medium efficiency, low
activity), oxidation, 3,4-
quinone formation (lower
activity); oxidation, 2,3-
quinone formation; C16α-
hydroxylation (high Km,
low activity)		 potent
activation		 71, 106,
121-130 		9721189,
8037457,
7826886,
9625734,
9054608,
9667077,
8930523,
11555828,
12865317,
15784278,
16112414,
17570247
CYP1A1 physiologi
cal
compound		 estrogen estrone C2-hydroxylation (major
reaction, medium Km, low
activity), oxidation, 2,3-
quinone formation; C4-
hydroxylation (medium
Km, low activity, or
medium activity); C16α-
hydroxylation (minor
reaction, very low
activity)		 activation 49, 127,
130, 131 		10426814,
12865317,
17570247,
15805301
CYP1A1 chemical PAH, metabolite fluoranthene-2,3-diol oxidation activation 34, 43 16946553,
11502724
CYP1A1 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide oxidation (at high
concentrations)		 activation 87 20507880
CYP1A1 chemical PAH naphtho[1,2-k]fluoranthene oxidation activation 103 10613181
CYP1A1 chemical PAH naphtho[2,1-a]pyrene oxidation activation 103 10613181
CYP1A1 chemical PAH naphtho[2,3-a]pyrene oxidation activation 103 10613181
CYP1A1 chemical N-heterocyclic
aromatic hydrocarbon,
dibenzocarbazole		 N-
methyldibenzo[c,g]carbazole		 oxidation potent
activation		 88-91 10984687,
12034315,
15534862,
21809388
CYP1A1 chemical tobacco-specific
nitrosamine		 N’-nitrosoanabasine oxidation activation 132, 133 11774366,
12214673
CYP1A1 chemical nitrosamine N-nitrosodibutylamine (N, N-
dibutylnitrosamine)		 oxidation activation 134 11600130
CYP1A1 chemical nitrosamine N-nitrosodiethylamine (N, N-diethylnitrosamine) oxidation activation 132-134 11774366,
12214673,
11600130
CYP1A1 chemical nitrosamine N-nitrosodi-n-propylamine
(N-nitrosodipropylamine)		 oxidation activation 134 11600130
CYP1A1 chemical nitrosamine N-nitrosoethylbutylamine oxidation (major enzyme) activation 134 11600130
CYP1A1 chemical nitrosamine N-nitrosomethylbutylamine oxidation activation 134 11600130
CYP1A1 chemical nitrosamine N-nitrosomethylethylamine oxidation activation 134 11600130
CYP1A1 chemical nitrosamine N-nitrosomethylpropylamine oxidation activation 69, 134 16720019,
11600130
CYP1A1 chemical nitrosamine N-nitrosomorpholine oxidation activation 132, 133 11774366,
12214673
CYP1A1 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 oxidation activation 132, 133 11774366,
12214673
CYP1A1 chemical nitrosamine N-nitrosopyrrolidine Cα-hydroxylation (2-OH-
tetrahydrofuran
formation); oxidation		 activation 132, 133 11774366,
12214673
CYP1A1 chemical azoarylamine o-aminoazotoluene oxidation activation 41, 66 8674051,
9685642
CYP1A1 chemical diphenylketone,
metabolite		 p-benzoylphenol,4-
hydroxybenzophenone		 oxidation activation 102 12160905
CYP1A1 chemical PAH phenanthrene oxidation to 1,2- (major
reaction), 9,10-, and 3,4-
dihydrodiols (minor
reactions) and phenols, at
high concentration		 activation 46, 135 7581497,
19766613
CYP1A1 chemical aza-aromatic Sudan I oxidation, major enzyme activation 136, 137 12384524,
17159775
CYP1A2 chemical PAH, metabolite (±)-, (−)-, and (+)-
benzo[a]pyrene-7,8-
dihydrodiol		 trans-(anti)-7,8-
dihydroxy-9,10-epoxy-
7,8,9,10-tetrahydro-
formation; oxidation		 activation 13, 34, 41-
43, 120,
138, 139 		2509067,
16946553,
8674051,
7955101,
1502724,
16485905,
9014198,
2803520
CYP1A2 chemical triazole 1-aminobenzotriazole (1-
ABT)		 oxidation activation 140 17584015
CYP1A2 chemical arylamine, metabolite
of 1-nitropyrene		 1-aminopyrene oxidation activation 54, 141-
144 		11525925,
15728263,
15843388,
17158518,
9860501
CYP1A2 chemical PAH, aza-aromatic 1-azabenzo[a]pyrene oxidation potent
activation		 145 14729370
CYP1A2 chemical arylamine, metabolite 2-acetylaminofluorene (2-
AAF)		 N-hydroxylation (major
enzyme), oxidation		 potent
activation		 12, 41, 57,
107, 139,
146, 147 		2655891,
8674051,
15279838,
1486866,
2803520,
11375903,
15450435
CYP1A2 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 N-hydroxylation,
oxidation (high activity,
major enzyme, major
reaction)		 potent
activation		 57-61, 63,
107, 146,
148-156,
157 		15279838,
9111224,
9855011,
21081470,
11377247,
8200083,
1486866,
11375903,
8082563,
1913651,
9705755,
11013410,
10503887,
12351158,
14744142,
14725854,
15073045,
16167840
CYP1A2 chemical heterocyclic amine 2-amino-3,4,8-
trimethylimidazo[4,5-
]quinoxaline (DiMeIQx)		 N-hydroxylation potent
activation		 107 1486866
CYP1A2 chemical heterocyclic amine 2-amino-3,4-
dimethylimidazo[4,5-
f]quinolone (MeIQ)		 N-hydroxylation;
oxidation (major enzyme)		 potent
activation		 12, 41, 56,
61-63, 71,
94, 107,
120, 150,
151, 154,
155, 158 		2655891,
8674051,
21786339,
11377247,
11473383,
8200083,
9721189,
8200084,
1486866,
16485905,
9705755,
11013410,
14744142,
14725854,
10861951
CYP1A2 chemical heterocyclic amine 2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (MeIQx)		 N-hydroxylation (major
enzyme, high activity)		 potent
activation		 12, 41, 58,
61-63, 94,
107, 151-
155 		2655891,
8674051,
9111224,
11377247,
11473383,
8200083,
8200084,
1486866,
11013410,
10503887,
12351158,
14744142,
14725854
CYP1A2 chemical arylamine,
heterocyclic		 2-amino-3-methyl-9H-
pyrido[2,3-b]indole
(MeAαC)		 N-hydroxylation,
oxidation		 potent
activation		 159 14729582
CYP1A2 chemical heterocyclic amine 2-amino-3-
methylimidazo[4,5-
f]quinolone (IQ)		 N-hydroxylation,
oxidation (high activity,
major enzyme)		 potent
activation		 12, 41, 58,
61, 65, 71,
141-144,
151, 154,
155, 160-
163 		2655891,
8674051,
9111224,
11377247,
9918136,
9721189,
15728263,
15843388,
17158518,
9860501,
11013410,
14744142,
14725854,
1486866,
2813353,
9675256,
10023085,
15089095
CYP1A2 chemical heterocyclic amine 2-amino-6-
methyldipyrido[1,2-a:3′,2′-d]-
imidazole (Glu-P-1)		 N-hydroxylation,
oxidation (high activity,
major enzyme)		 potent
activation		 12, 41, 61,
107, 139,
154, 155,
160 		2655891,
8674051,
11377247,
1486866,
2803520,
14744142,
14725854,
2813353
CYP1A2 chemical heterocyclic amine 2-amino-α-carboline oxidation activation 149, 164 1913651,
8801053
CYP1A2 chemical arylamine 2-aminoanthracene N-hydroxylation,
oxidation (major enzyme)		 potent
activation		 12, 41, 61,
107, 139,
141-144,
162, 165 		2655891,
8674051,
11377247,
1486866,
2803520,
15728263,
15843388,
17158518,
9860501,
10023085,
9477228
CYP1A2 chemical heterocyclic amine 2-aminodipyrido[1,2-a:3,2′-
d]-imidazole (Glu-P-2)		 oxidation activation 12, 107,
139 		2655891,
1486866,
2803520
CYP1A2 chemical arylamine 2-aminofluorene (2-AF) N-hydroxylation,
oxidation (major enzyme,
high activity)		 potent
activation		 12, 41, 61,
107, 139,
166-168 		2655891,
8674051,
11377247,
1486866,
2803520,
15840428,
16372832,
10727902
CYP1A2 chemical arylamine 2-naphthylamine (β-
naphthylamine)		 N-hydroxylation,
oxidation		 activation 12, 61, 107,
147, 160 		2655891,
11377247,
1486866,
15450435,
2813353
CYP1A2 chemical nitroarene 2-nitrofluoranthene nitroreduction activation 53 11113705
CYP1A2 chemical nitrosamine 3-(N-
nitrosomethylamino) propiona
ldehyde		 oxidation activation 68 15725615
CYP1A2 chemical nitroarene 3,6-dinitrobenzo[e]pyrene nitroreduction activation 70 19393727
CYP1A2 chemical nitroarene 3-acetylaminobenzanthrone N-hydroxylation
(concentration dependent)		 activation 79 12740904
CYP1A2 chemical heterocyclic amine 3-amino-1,4-dimethyl-5H-
pyrido[4,3-b]indole (Trp-P-1)		 N-hydroxylation;
oxidation (major enzyme)		 activation 12, 41, 61,
139, 151 		2655891,
8674051,
11377247,
2803520,
11013410
CYP1A2 chemical heterocyclic amine 3-amino-1-methyl-5H-
pyrido[4,3-b]indole (Trp-P-2)		 N-hydroxylation,
oxidation (major enzyme)		 activation 12, 41, 61,
62, 94, 107,
151, 160 		2655891,
8674051,
11377247,
11473383,
8200084,
1486866,
11013410,
2813353
CYP1A2 chemical arylamine, metabolite 3-aminobenzanthrone N-hydroxylation (major
enzyme, concentration
dependent)		 activation 72, 73 15885895,
16601755
CYP1A2 chemical azoaromatic amine 3-methoxy-4-
aminoazobenzene		 oxidation activation 41 8674051
CYP1A2 chemical arylamine 3′-methyl-4-
dimethylaminazobenzene		 oxidation potent
activation		 169 10720750
CYP1A2 chemical nitroarene 3-nitrobenzanthrone nitroreduction activation 73, 79, 80 16601755,
12740904,
12782579
CYP1A2 chemical nitroarene 3-nitrofluoranthene nitroreduction activation 53 11113705
CYP1A2 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl N-hydroxylation,
oxidation		 activation 12, 41, 58,
107, 147,
160, 170,
171 		2655891,
8674051,
9111224,
1486866,
15450435,
2813353,
9163700,
16988941
CYP1A2 natural
compound		 furanoterpene
produced by sweet
potatoes infected with
Fusarium solani;
pulmonary toxin,
alkylating		 4-ipomeanol oxidation (major enzyme) activation 172, 173 1651809,
15892579
CYP1A2 chemical nitroarene 4-nitropyrene 4-aminopyrene formation
(nitroreduction)		 activation 174 10197616
CYP1A2 chemical PAH, metabolite 5,6-dimethylchrysene-1,2-
diol		 oxidation activation 34, 43, 81 16946553,
11502724,
14720319
CYP1A2 chemical N-heterocyclic
aromatic hydrocarbon,		 5,9-
dimethyldibenzo[c,g]carbazol
e		 oxidation activation 88-91 10984687,
12034315,
15534862,
21809388
CYP1A2 chemical PAH, metabolite 5-methylchrysene-1,2-diol oxidation activation 31, 34, 43,
81 		16946553,
8674051,
11502724,
14720319
CYP1A2 chemical arylamine 6-aminochrysene oxidation activation 41, 66, 84,
85, 141-
144 		8674051,
9685642,
8118930,
8330339,
15728263,
15843388,
17158518,
9860501
CYP1A2 chemical arylamine, metabolite 6-aminochrysene-1,2-diol diol epoxide formation;
oxidation		 activation 41, 84, 85 8674051,
8118930,
8330339
CYP1A2 chemical PAH 7,12-
dimethylbenz[a]anthracene		 oxidation activation 43, 81, 86 11502724,
14720319,
12584184
CYP1A2 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 oxidation activation 34, 43, 81 16946553,
11502724,
14720319
CYP1A2 chemical N-heterocyclic
aromatic hydrocarbon		 7H-dibenzo[c,g]carbazole oxidation activation 88-90 10984687,
12034315,
15534862
CYP1A2 chemical PAH, aza-aromatic 7-methylbenz[c]acridine 3,4-dihydrodiol formation activation 92 7866988
CYP1A2 chemical PAH, aza-aromatic 7-methylbenz[c]acridine oxidation activation 92 7866988
CYP1A2 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) epoxidation (both exo-
8,9- and endo-8,9-),
oxidation		 activation 11, 12, 41,
42, 57, 61,
93, 94, 162,
175-182 		2492107,
2509067,
8674051,
7955101,
15279838,
11377247,
7923587,
8200084,
10023085,
2162057,
766804,
8261428,
12079611,
1902334,
11782366,
16385575,
16608170
CYP1A2 chemical heterocyclic amine aminomethylphenylnorharma
n		 N-hydroxylation activation 95 17067997
CYP1A2 chemical arylamine,
heterocyclic		 aminophenylharman N-hydroxylation activation 95 17067997
CYP1A2 chemical arylamine,
heterocyclic		 aminophenylnorharman N-hydroxylation activation 95 17067997
CYP1A2 natural
compound		 phenanthroic acid
derivative;
nephrotoxin, found in
the Aristolochiaceae
family of plants		 aristolochic acid I nitroreduction potent
activation		 96-99 11511187,
15386410,
16125300,
22086975
CYP1A2 natural
compound		 phenanthroic acid
derivative;
nephrotoxin, found in
the Aristolochiaceae
family of plants		 aristolochic acid II nitroreduction potent
activation		 96-99 11511187,
15386410,
16125300,
22086975
CYP1A2 chemical PAH, metabolite benz[a]anthracene-3,4-diol oxidation activation 34, 43, 81 16946553,
11502724,
14720319
CYP1A2 chemical diphenylmethanol,
metabolite		 benzhydrol oxidation activation 102 12160905
CYP1A2 chemical PAH, metabolite benzo[b]fluoroanthene-9,10-
diol		 oxidation activation 34, 41, 43,
81 		16946553,
8674051,
11502724,
14720319
CYP1A2 chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol		 oxidation activation 43 11502724
CYP1A2 chemical PAH, metabolite benzo[g]chrysene-11,12-diol oxidation activation 34, 43, 81 16946553,
11502724,
14720319
CYP1A2 chemical aromatic ketone,
diphenyl ketone		 benzophenone oxidation activation 102 12160905
CYP1A2 chemical PAH, metabolite chrysene-1,2-diol oxidation activation 34, 41, 81 16946553,
11502724,
14720319
CYP1A2 drug imidazole; anticancer,
alkylating		 dacarbazine N-demethylation (major
enzyme)		 potent
activation		 111 10473105
CYP1A2 natural
compound		 bicyclic monoterpene Δ3-carene epoxidation (high Km,
medium activity)		 activation 183 16379671
CYP1A2 chemical PAH dibenz[a,h]anthracene 3,4-dihydrodiol formation activation 184 8638931
CYP1A2 chemical PAH, aza-aromatic dibenz[a,j]acridine 3,4-dihydrodiol formation activation 92 7866988
CYP1A2 chemical PAH dibenzo[a,l]pyrene (−)-anti-11,12-
dihydrodiol-13,14-
epoxide formation,
oxidation		 activation 81 14720319
CYP1A2 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 oxidation activation 34, 71, 81 16946553,
9721189,
14720319
CYP1A2 drug pyrido-carbazole;
antineoplastic,
alkaloid,
Apocyanaceae plant
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine hydroxylation, C12- and
C13- (low activity)		 activation 39, 40,
185-189 		16936898,
21753906,
11755121,
12123750,
15548707,
17197724,
21683692
CYP1A2 physiologi
cal
compound		 estrogen 17β-estradiol C2-hydroxylation (major
reaction, medium Km,
medium activity, medium
efficiency), major
metabolite and major
enzyme in liver; C4-
hydroxylation (minor
reaction); C16α-
hydroxylation (major
enzyme, high Km, no
activity, or low activity)		 activation 71, 106,
122-124,
126-129,
190-194 		9721189,
8037457,
9625734,
9054608,
9667077,
11555828,
12865317,
15784278,
16112414,
1449532,
9635876,
11454902,
11741520,
14703066
CYP1A2 natural
compound		 alkenylbenzene;
occurs in a variety of
foods including
essential oils of
tarragon, sweet basil,
sweet fennel, anis		 estragole C1′-hydroxylation (major
enzyme, medium Km, low
activity)		 potent
activation		 195-197 17407329,
15914212,
21459083
CYP1A2 physiologi
cal
compound		 estrogen estrone C2-hydroxylation
(medium Km, high
activity, major
metabolite); C4-
hydroxylation (medium
Km, medium activity, very
low activity); C16α-
hydroxylation (minor
reaction, very low
activity)		 activation 49, 122,
123, 127,
128, 191,
192, 198 		10426814,
9625734,
9054608,
12865317,
15784278,
9635876,
11454902,
16537715
CYP1A2 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide oxidation (at high
concentration)		 activation 87 20507880
CYP1A2 natural
compound		 phenylpropene; from
Rhizoma
acorigraminei 		methyleugenol C1′-hydroxylation
(medium Km, major
enzyme)		 activation 196, 199 15914212,
16411663
CYP1A2 chemical arylamine, metabolite N-acetyl-N-hydroxy-3-
aminobenzanthrone		 oxidation, at higher
concentrations		 activation 79 12740904
CYP1A2 chemical PAH naphthalene oxidation activation 200 11356140
CYP1A2 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-3-
aminobenzanthrone		 reduction to amine activation 79 12740904
CYP1A2 chemical N-heterocyclic
aromatic hydrocarbon		 N-
methyldibenzo[c,g]carbazole		 oxidation activation 88-91 10984687,
12034315,
15534862,
21809388
CYP1A2 chemical nitrosamine N-nitrosoethylbutylamine oxidation activation 134 11600130
CYP1A2 chemical nitrosamine N-nitrosomethylbutylamine oxidation activation 134 11600130
CYP1A2 chemical nitrosamine N-nitrosomethylethylamine oxidation activation 134 11600130
CYP1A2 chemical nitrosamine N-nitrosomethylpropylamine oxidation activation 69, 134 16720019,
11600130
CYP1A2 chemical nitrosamine N-nitrosopyrrolidine Cα-hydroxylation (2-OHtetrahydrofuran
formation)		 activation 132, 133 11774366,
12214673
CYP1A2 chemical azoarylamine o-aminoazotoluene oxidation activation 41, 66 8674051,
9685642
CYP1A2 chemical o-methoxyaniline o-anisidine (2-
methoxyaniline)		 N-hydroxylation (major
enzyme with recombinant
model), oxidation		 activation 147, 201 15450435,
15828049
CYP1A2 chemical diphenylketone,
metabolite		 p-benzoylphenol (4-
hydroxybenzophenone)		 oxidation activation 102 12160905
CYP1A2 chemical PAH phenanthrene oxidation to 1,2- (major
reaction), 3,4-, and 9,10-
dihydrodiols and phenols		 activation 46, 135 7581497,
19766613
CYP1A2 natural
compound		 furanoxanthone;
mycotoxin, produced
by Aspergillus species		 sterigmatocystin oxidation activation 41 8674051
CYP1A2 chemical aromatic hydrocarbon,
alkyl benzene		 styrene (vinyl benzene) oxidation, 7,8-oxide
formation		 activation 202-207 9253143,
7696548,
11407535,
12616646,
12834847,
18266326
CYP1B1 chemical PAH, metabolite (±)-, (−)-, and (+)-
benzo[a]pyrene-7,8-
dihydrodiol		 trans-(anti)-7,8-
dihydroxy-9,10-epoxy-
7,8,9,10-tetrahydro-
formation, trans-diol
epoxide form (low Km,
high activity, high
efficiency); oxidation		 potent
activation		 26, 31, 32,
34, 41, 43,
49, 52, 120,
208-210 		16411658,
15720144,
17295519,
16946553,
8674051,
11502724,
10426814,
21028851,
16485905,
12628515,
12807732,
16551781
CYP1B1 chemical nitroarene 1,8-dinitropyrene nitroreduction potent
activation		 53 11113705
CYP1B1 chemical arylamine, metabolite
of 1-nitropyrene		 1-aminopyrene oxidation potent
activation		 54 11525925
CYP1B1 chemical PAH 2,3-dihydroxy-2,3-
dihydrofluoranthene		 oxidation activation 66 9685642
CYP1B1 chemical heterocyclic amine 2-amino-3,4-
dimethylimidazo[4,5-
f]quinolone (MeIQ)		 N-hydroxylation,
oxidation		 activation 41, 49, 61,
100, 210,
211 		8674051,
10426814,
11377247,
11502724,
16551781,
11719446
CYP1B1 chemical heterocyclic amine 2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (MeIQx)		 N-
hydroxylation, oxidation		 activation 41, 49, 61 8674051
10426814,
11377247
CYP1B1 chemical heterocyclic amine 2-amino-3-
methylimidazo[4,5-
f]quinolone (IQ)		 N-hydroxylation,
oxidation		 activation 41, 49, 61,
65, 100 		8674051,
10426814,
11377247,
9918136,
11502724
CYP1B1 chemical arylamine 2-aminoanthracene N-hydroxylation,
oxidation (high activity)		 potent
activation		 41, 61, 100,
210 		8674051,
11377247,
11502724,
16551781
CYP1B1 chemical arylamine 2-aminofluorene (2-AF) N-hydroxylation,
oxidation		 potent
activation		 41, 49, 61,
100, 210 		8674051,
10426814,
11377247,
11502724,
16551781
CYP1B1 chemical nitroarene 2-nitrofluoranthene nitroreduction potent
activation		 53 11113705
CYP1B1 chemical nitroarene 2-nitropyrene 2-aminopyrene formation
(nitroreduction)		 potent
activation		 41, 100 8674051,
11502724
CYP1B1 chemical nitrosamine 3-(N-
nitrosomethylamino) propiona
ldehyde		 oxidation activation 68 15725615
CYP1B1 chemical heterocyclic amine 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) N-hydroxylation,
oxidation		 potent
activation		 41, 49, 61,
66, 71, 100,
210 		8674051,
10426814,
11377247,
9685642,
9721189,
11502724,
16551781
CYP1B1 chemical heterocyclic amine 3-amino-1-methyl-5H-
pyrido[4,3-b]indole (Trp-P-2)		 N-hydroxylation;
oxidation		 activation 41, 49, 61,
62, 66, 71,
100 		8674051,
10426814,
11377247,
11473383,
9685642,
11502724
CYP1B1 chemical arylamine, metabolite 3-aminobenzanthrone N-hydroxylation activation 212 15310241
CYP1B1 chemical azoaromatic amine 3-methoxy-4-
aminoazobenzene		 oxidation potent
activation		 41, 49, 66,
100, 210 		8674051,
10426814,
9685642,
11502724,
16551781
CYP1B1 chemical nitroarene 3-nitrofluoranthene nitroreduction activation 53 11113705
CYP1B1 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 oxidation activation 132, 133,
213-217 		11774366,
12214673,
1312898,
7595636,
8806763,
10803680,
9106248
CYP1B1 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl N-hydroxylation;
oxidation		 activation 41, 218 8674051,
19274671
CYP1B1 chemical PAH, metabolite 5,6-dimethylchrysene-1,2-
diol		 oxidation activation 34, 41, 43,
49, 66, 81,
210 		16946553,
8674051,
11502724,
10426814,
9685642,
14720319,
16551781
CYP1B1 chemical PAH 5-methylchrysene oxidation activation 83, 210 18992797
16551781
CYP1B1 chemical PAH, metabolite 5-methylchrysene-1,2-diol oxidation (medium Km,
high activity, high
efficiency)		 potent
activation		 34, 41, 43,
49, 66, 81,
83, 120,
210		 16946553,
8674051,
11502724,
10426814,
9685642,
14720319,
18992797,
16485905,
16551781
CYP1B1 chemical arylamine 6-aminochrysene oxidation potent
activation		 41, 43 8674051,
11502724
CYP1B1 chemical arylamine, metabolite 6-aminochrysene-1,2-diol diolepoxide formation,
oxidation		 potent
activation		 41, 84, 85 8674051,
8118930,
8330339
CYP1B1 chemical nitroarene 6-nitrochrysene nitroreduction; 5,6-
quinone formation		 activation 41, 43, 219 8674051,
11502724,
8481905
CYP1B1 chemical PAH 7,12-
dimethylbenz[a]anthracene		 oxidation (low Km, high
activity and efficiency)		 activation 43, 49, 81,
86, 210 		11502724,
10426814,
14720319,
12584184,
16551781
CYP1B1 chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 3,4-dihydrodiol-1,2-
epoxide formation
(medium Km, high
activity, high efficiency);
oxidation		 potent
activation		 34, 41, 43,
49, 66, 81 		16946553,
8674051,
11502724,
10426814,
9685642,
14720319
CYP1B1 chemical PAH, metabolite 9-hydroxybenzo[a]pyrene oxidation activation 43 11502724
CYP1B1 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) oxidation activation 61, 210,
217 		11377247,
16551781,
9106248
CYP1B1 chemical diphenylmethanol,
metabolite		 benzhydrol oxidation activation 102 12160905
CYP1B1 chemical PAH benzo[a]pyrene trans-7,8-dihydroxy-9,10-
epoxy-7,8,9,10-
tetrahydro- formation
(medium Km, high
activity, high efficiency);
1,6-,3,6-dione (quinone
form., low activity);
oxidation (major enzyme)		 activation 34, 41, 43,
49, 52, 61,
81, 104,
208, 210,
220-222 		16946553,
8674051,
11502724,
10426814,
21028851,
11377247,
14720319,
9806168,
12628515,
16551781,
10409402,
11465393,
15958554
CYP1B1 chemical PAH, metabolite benzo[b]fluoroanthene-9,10-
diol		 oxidation activation 34, 43, 49,
50, 81 		16946553,
8674051,
11502724,
10426814,
14720319
CYP1B1 chemical PAH benzo[c]phenanthrene dihydrodiol 3,4-, 1,2-
epoxide formation (major
enzyme); oxidation		 activation 43, 81, 109,
217, 223 		11502724,
14720319,
11409939,
9168260,
21781864
CYP1B1 chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol		 dihydrodiol 3,4-, 1,2-
epoxide formation		 activation 43, 49 11502724,
10426814
CYP1B1 chemical PAH, metabolite benzo[g]chrysene-11,12-diol oxidation potent
activation		 34, 41, 43,
49, 66, 81 		16946553,
8674051,
11502724,
10426814,
9685642,
14720319
CYP1B1 chemical aromatic ketone,
diphenyl ketone		 benzophenone oxidation activation 102 12160905
CYP1B1 chemical PAH, metabolite chrysene-1,2-diol oxidation potent
activation		 34, 41, 43,
49, 66, 81,
210 		16946553,
8674051,
11502724,
10426814,
9685642,
14720319,
16551781
CYP1B1 chemical PAH cyclopenta[c,d]pyrene oxidation activation 217 9106248
CYP1B1 chemical PAH, aza-aromatic dibenz[a,h]acridine 10,11-diol formation activation 111 15144224
CYP1B1 chemical PAH dibenzo[a,l]pyrene (−)-anti-11,12-
dihydrodiol-13,14-
epoxide formation
(medium Km, high
activity, high efficiency);
oxidation		 potent
activation		 43, 81,
113-119,
208, 210,
224 		11502724,
14720319,
9625737,
10207125,
10493514,
10506751,
8968059,
16581046,
17509623,
12628515,
16551781,
17623886
CYP1B1 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 11,12-dihydrodiol-13,14-
epoxide formation
(medium Km, high
activity, high efficiency)		 potent
activation		 34, 41, 43,
49, 71, 81,
113-115,
118, 120,
208, 210 		16946553,
8674051,
11502724,
10426814,
9721189,
14720319,
9625737,
10207125,
10493514,
16581046,
17509623,
16485905,
12628515,
16551781
CYP1B1 drug pyrido-carbazole;
antineoplastic,
alkaloid,
Apocyanaceae plant
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine oxidation activation 39, 185-
188 		16936898,
11755121,
12123750,
15548707,
17197724
CYP1B1 physiologi
cal
compound		 estrogen 17β-estradiol C4-hydroxylation (major
enzyme, medium Km,
medium activity, medium
and low efficiency),
oxidation, 3,4-quinone
formation; C2-
hydroxylation (low
activity, minor reaction),
oxidation, 2,3-quinone
formation; C16α-
hydroxylation (minor
enzyme, medium and high
Km, low activity)		 potent
activation		 49, 71,
121-130,
194, 211,
221, 225-
228 		10426814,
9721189,
7826886,
9625734,
9054608,
9667077,
8930523,
11555828,
12865317,
15784278,
16112414,
17570247,
14703066,
11719446,
11465393,
8790407,
7568105,
10862525,
10910054
CYP1B1 physiologi
cal
compound		 estrogen estrone C4-hydroxylation (low
Km, major reaction); C2-
hydroxylation (low
activity, minor reaction),
oxidation, 2,3-quinone
formation;		 potent
activation		 49, 127,
128, 130,
198 		10426814,
12865317,
15784278,
17570247,
16537715
CYP1B1 chemical nitrosamine N-nitrosodiethylamine (N,N-
diethylnitrosamine)		 oxidation activation 132-134 11774366,
12214673,
11600130
CYP1B1 chemical nitrosamine N-nitrosoethylbutylamine oxidation activation 134 11600130
CYP1B1 chemical nitrosamine N-nitrosomethylbutylamine oxidation activation 134 11600130
CYP1B1 chemical nitrosamine N-nitrosomethylpropylamine oxidation activation 69, 134 16720019,
11600130
CYP1B1 chemical nitrosamine N-nitrosomorpholine oxidation activation 132, 133 11774366,
12214673
CYP1B1 chemical nitrosamine N-nitrosopyrrolidine Cα-hydroxylation (2-OHtetrahydrofuran
formation), oxidation		 activation 132, 133 11774366,
12214673
CYP1B1 chemical diphenylketone,
metabolite		 p-benzoylphenol,4-
hydroxybenzophenone		 oxidation activation 102 12160905
CYP1B1 chemical PAH phenanthrene oxidation to 9,10- (major
reaction), and 1,2- and
3,4- (minor reaction)
dihydrodiols and phenols		 activation 135 19766613
CYP1B1 chemical nitroarene 1-nitropyrene 1-aminopyrene form.
(nitroreduction), at low
concentrations,
epoxidation C4,5-, at high
concentration		 potent
activation		 53, 54, 229 11113705,
11525925,
15310239
CYP2A6 chemical haloalkane 1, 2-dibromoethane (ethylene
dibromide)		 oxidation to 2-
bromoacetaldehyde		 activation 230 8870687
CYP2A6 chemical diene 1,3-butadiene butadiene monoxide
(epoxybutene) formation
(high activity)		 activation 231-233 7586124,
8901879,
9016811
CYP2A6 chemical nitrile, herbicide 2,6-dichlorobenzonitrile
(dichlobenil)		 epoxidation, C2,3- activation 234, 235 8649351,
8863822
CYP2A6 chemical arylamine 2,6-dimethylaniline N-hydroxylation (at
higher concentrations),
major enzyme		 activation 236 11409937
CYP2A6 chemical nitrosamine 3-(N-
nitrosomethylamino) propiona
ldehyde		 oxidation activation 68 15725615
CYP2A6 chemical nitrosamine 3-(N-
nitrosomethylamino) propioni
trile		 oxidation (at high
concentrations, major
enzyme)		 potent
activation		 68, 69 15725615,
16720019
CYP2A6 chemical arylamine, metabolite 3-aminobenzanthrone N-hydroxylation activation 212 15310241
CYP2A6 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 Cα-hydroxylationmethylene
(lactol/acid
formation or Cα-methyl
(diol/acid formation)		 activation 170, 237,
238 		9163700,
12975327,
21473878
CYP2A6 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 Cα-hydroxylationmethylene
(keto aldehyde
and keto alcohol
formation), high Km, low
activity, oxidation		 activation 66, 132-
134, 141-
143, 213-
216, 238-
246 		9685642,
11774366,
12214673,
11600130,
15728263,
15843388,
17158518,
1312898,
7595636,
8806763,
10803680,
11016631,
15333516,
17671098,
21473878,
10837014,
11080669,
12920169,
1423839
CYP2A6 chemical arylamine 4,4′-methylene bis(2-
chloroaniline) (MOCA)		 oxidation, N-
hydroxylation		 activation 65, 106,
248, 249 		9685642,
1486866,
1944238,
1740010
CYP2A6 chemical arylamine 6-aminochrysene oxidation activation 248 1944238
CYP2A6 chemical diphenylmethanol,
metabolite		 benzhydrol oxidation (major enzyme) activation 102 12160905
CYP2A6 chemical aromatic ketone,
diphenyl ketone		 benzophenone oxidation (major enzyme) activation 102 12160905
CYP2A6 chemical aliphatic epoxide,
metabolite		 butadiene monoxide (1,2-
epoxy-3-butene)		 diepoxybutane meso-
(major) and (±)-
formation (at high
concentrations)		 activation 231-233 7586124,
8901879,
9016811
CYP2A6 chemical haloalkane chloroform
(trichloromethane)		 dehalogenation, reductive
(at high concentrations);
oxidation (major enzyme
at high concentrations)		 activation 250 12584152
CYP2A6 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (minor
enzyme, high Km);
oxidation		 activation 101, 108,
251-254 		11377097,
19501186,
8242617,
9010702,
10348794,
10692561
CYP2A6 natural
compound		 alkenylbenzene;
occurs in a variety of
foods including
essential oils of
tarragon, sweet basil,
sweet fennel, anis		 estragole C1′-hydroxylation (major
enzyme, medium Km,
medium activity)		 potent
activation		 195, 197 17407329,
21459083
CYP2A6 chemical phosphoramide hexamethylphosphoramide oxidation, formaldehyde
production		 activation 235, 255 8863822,
9007030
CYP2A6 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation (minor
reaction, high Km),
oxidation (at high
concentration)		 activation 87, 247,
253 		20507880,
8242617,
10348794
CYP2A6 natural
compound		 furanocoumarin; anti-
psoriatic,
photosensitizer, found
in several species of
plants		 methoxalen (8-
methoxypsoralen,
xanthotoxin)		 epoxidation
(furanoepoxide
formation) and hydrolysis		 activation 140 17584015
CYP2A6 chemical tobacco-specific
nitrosamine		 N’-nitrosoanabasine oxidation activation 132, 133 11774366,
12214673
CYP2A6 chemical tobacco-specific
nitrosamine		 N’-nitrosoanatabine oxidation activation 132, 133 11774366,
12214673
CYP2A6 chemical nitrosamine N-nitrosodibutylamine (N, N-
dibutylnitrosamine)		 oxidation activation 244, 134 10837014,
11600130
CYP2A6 chemical nitrosamine N-nitrosodiethylamine (N,N-
diethylnitrosamine)		 oxidation potent
activation		 106, 132-
134, 141-
144, 245-
247 		1486866,
11774366,
12214673,
11600130,
15728263,
15843388,
17158518,
9860501,
10837014,
11080669,
1423839
CYP2A6 chemical nitrosamine N-nitrosodi-n-propylamine
(N-nitrosodipropylamine)		 oxidation potent
activation		 134, 141-
143, 244 		11600130,
15728263,
15843388,
17158518,
10837014
CYP2A6 chemical nitrosamine N-nitrosoethylbutylamine oxidation (major enzyme) potent
activation		 134, 244 11600130,
10837014
CYP2A6 chemical nitrosamine N-nitrosomethylbutylamine oxidation (major enzyme) potent
activation		 134, 244 11600130,
10837014
CYP2A6 chemical nitrosamine N-nitrosomethylethylamine oxidation potent
activation		 134, 243 11600130,
10837014
CYP2A6 chemical nitrosamine N-nitrosomethylphenylamine oxidation activation 134, 243,
245 		11600130,
10837014,
11080669
CYP2A6 chemical nitrosamine N-nitrosomethylpropylamine oxidation activation 68, 134,
244 		16720019,
11600130,
10837014
CYP2A6 chemical nitrosamine N-nitrosomorpholine oxidation (major enzyme) activation 132, 133 11774366,
12214673
CYP2A6 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-nitrosonornicotine, NNN) hydroxylation C5′- (lactol
formation, medium Km,
high to medium activity),
oxidation (major enzyme)		 activation 132-134,
244, 256-
258 		11774366,
12214673,
11600130,
15651850,
10837014,
9276639,
7646564
CYP2A6 chemical nitrosamine N-nitrosopiperidine Cα-hydroxylation (2-OH-
tetrahydropyran and 2-
OH-5-
methyltetrahydropyran
formation), major
enzyme; oxidation		 activation 132, 133,
258 		11774366,
12214673,
15651850
CYP2A6 chemical nitrosamine N-nitrosopyrrolidine, Cα-hydroxylation (2-OH-
tetrahydrofuran
formation); oxidation
(major enzyme)		 activation 132-134,
244, 258 		11774366,
12214673,
11600130,
15651850,
10837014
CYP2A6 chemical diphenylketone,
metabolite		 p-benzoylphenol (4-
hydroxybenzophenone)		 oxidation (major enzyme) activation 102 12160905
CYP2A6 natural
compound		 Methylenedioxypheny
l (benzodioxole)		 safrole C1′-hydroxylation (major
enzyme at low
concentrations), medium
Km, medium activity		 activation 195, 196,
259, 260 		17407329,
15914212,
15377158,
15310247
CYP2A13 chemical nitrosamine 3-(N-
nitrosomethylamino) propiona
ldehyde		 oxidation (major enzyme) potent
activation		 68 15725615
CYP2A13 natural
compound		 indole, alkylating,
pulmonary toxin; in
higher concentrations
in mammalian
digestive tract and coal
tar		 3-methylindole (skatole) dehydrogenation
(desaturation, 3-
methyleneindolenine
form., low Km, medium
activity, high efficiency),
epoxidation (3-
methyloxindole
formation)		 potent
activation		 77, 261 20795680,
19608696
CYP2A13 chemical nitrosamine 3-N-nitrosoguvacoline oxidation (major enzyme) activation 68, 69 15725615,
16720019
CYP2A13 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 Cα-hydroxylation-methyl
(keto alcohol formation),
major enzyme, medium
Km, medium activity, or
high activity		 potent
activation		 237-240,
262-266 		11016631,
12975327,
15333516,
15528319,
15962925,
12130698,
16917071,
17671098,
19074523,
21473878
CYP2A13 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl N-hydroxylation;
oxidation		 activation 58, 171 9111224,
16988941
CYP2A13 chemical difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) epoxidation 8,9-,
oxidation		 potent
activation		 181, 265 16385575,
16917071
CYP2A13 natural
compound		 furanocoumarin; anti-
psoriatic,
photosensitizer, found
in bergamot essential
oil, in other citrus
essential oils, and in
grapefruit juice		 bergapten, 5-
methoxypsoralen		 epoxidation and
hydrolysis to dihydrodiol		 activation 267 20798279
CYP2A13 chemical nitrosamine N-nitrosomethylpropylamine oxidation potent
activation		 69, 134 16720019,
11600130
CYP2A13 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 hydroxylation C5′- (lactol
formation, medium Km,
high activity) and C2′-
(keto alcohol formation,
medium Km, low activity)		 activation 258, 266 19074523,
15651850
CYP2A13 chemical nitrosamine N-nitrosopiperidine Cα-hydroxylation (2-OH-
tetrahydropyran and 2-
OH-5-methyl
tetrahydrofuran
formation)		 activation 258 15651850
CYP2A13 chemical nitrosamine N-nitrosopyrrolidine Cα-hydroxylation (2-OH-
tetrahydrofuran
formation)		 activation 258 15651850
CYP2A13 chemical aromatic hydrocarbon,
alkyl benzene		 styrene (vinyl benzene) oxidation, 7,8-oxide
formation		 activation 207 18266326
CYP2B6 chemical haloalkane 1, 2-dibromoethane (ethylene
dibromide)		 oxidation to 2-
bromoacetaldehyde		 activation 230 8870687
CYP2B6 chemical haloalkane 2, 2-dichloro-1,1,1-
trifluoroethane (HCFC-123)		 oxidation activation 268, 269 11684364,
11684365
CYP2B6 chemical arylamine, metabolite 3-aminobenzanthrone N-hydroxylation activation 212 15310241
CYP2B6 chemical azoaromatic amine 3-methoxy-4-
aminoazobenzene		 oxidation activation 270 7905383
CYP2B6 chemical nitroarene 3-nitrobenzanthrone nitroreduction potent
activation		 80 12782579
CYP2B6 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 hydroxylation, alphamethyl
(keto alcohol
form.), major reaction and
Cα-methylene (keto
aldehyde form.), minor
reaction		 activation 74, 213-
216, 252,
271, 272 		11360624,
1312898,
7595636,
8806763,
10803680,
12920169,
9280407,
16174803
CYP2B6 chemical unsaturated 4-vinyl-1-cyclohexene (S)-
and (R)-		 epoxidation 7,8- (major
reaction, stereoselective
for (R)-); epoxidation 1,2-		 activation 100, 273 11502734,
11159809
CYP2B6 chemical arylamine 6-aminochrysene oxidation activation 85, 270 8330339,
7905383
CYP2B6 chemical herbicide,
chloroacetamide		 alachlor oxidation activation 274 11133395
CYP2B6 chemical herbicide,
chloroacetamide		 butachlor oxidation activation 274 11133395
CYP2B6 chemical haloalkane chloroform
(trichloromethane)		 oxidation (at high conc.) activation 250 12584152
CYP2B6 drug azaphosporine;
anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (major
enzyme, major reaction,
high Km, high activity);
oxidation		 potent
activation		 74, 101,
108, 251-
254, 271,
275 		11360624,
11377097,
19501186,
8242617,
9010702,
10348794,
10692561,
9280407,
15919850
CYP2B6 chemical polycyclic aromatic
hydrocarbon (PAH)		 dibenz[a,h]anthracene 3,4-dihydrodiol form. activation 184 8638931
CYP2B6 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation
stereoselective for (S)-
(high Km, major enzyme),
oxidation (at high
concentrations)		 activation 87, 259,
261, 262,
275-278 		20507880,
8242617,
10348794,
10692561,
15919850,
10534317,
15821045,
16854777
CYP2B6 chemical herbicide,
chloroacetamide		 metolachlor oxidation activation 274 11133395
CYP2B6 chemical aziridine N, N’, N”-triethylene
thiophosphoramide
(thioTEPA)		 desulfuration, TEPA
formation (major enzyme)		 activation 140, 279 17584015,
12107550,
CYP2B6 chemical nitrosamine N-nitrosomorpholine oxidation activation 74 11360624
CYP2B6 chemical o-methoxyaniline o-anisidine (2-
methoxyaniline)		 N-hydroxylation activation 201 15828049
CYP2B6 chemical aromatic hydrocarbon,
alkyl benzene		 styrene (vinyl benzene) oxidation (major enzyme
in liver microsomes at
high concentration)		 activation 202-205,
2780		 9253143,
7696548,
11407535,
12616646,
16125881
CYP2C8 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 oxidation activation 132, 133 11774366,
12214673
CYP2C8 chemical haloalkane chloroform
(trichloromethane)		 dehalogenation reductive
(at high concentrations)		 activation 258 12584152
CYP2C8 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation (minor
enzyme, high Km),
oxidation (at high
concentrations)		 activation 87, 259,
261 		20507880,
8242617,
10348794
CYP2C8 chemical nitrosamine N-nitrosomethylbutylamine oxidation activation 134 11600130
CYP2C8 chemical nitrosamine N-nitrosomethylpropylamine oxidation activation 134 11600130
CYP2C8 chemical nitrosamine N-nitrosopyrrolidine Cα-hydroxylation (2-OH-
tetrahydrofuran
formation); oxidation		 activation 132, 133 11774366,
12214673
CYP2C8 chemical aromatic
hydrocarbons, alkyl
benzene		 styrene (vinyl benzene) oxidation (major enzyme
in liver microsomes at
high concentrations)		 activation 202-205,
280 		9253143,
7696548,
11407535,
12616646,
16125881
CYP2C9 chemical diene 1,3-butadiene butadiene monoxide
(epoxybutene) formation
(high activity)		 activation 231-233 7586124,
8901879,
9016811
CYP2C9 chemical triazole 1-aminobenzotriazole (1-
ABT)		 oxidation activation 140 17584015
CYP2C9 chemical PAH 7,12-
dimethylbenz[a]anthracene		 oxidation activation 43, 81, 87 11502724,
14720319,
20507880
CYP2C9 chemical PAH benzo[c]phenanthrene oxidation activation 81 14720319
CYP2C9 chemical aliphatic epoxide,
metabolite		 butadiene monoxide (1, 2-
epoxy-3-butene)		 diepoxybutane meso- and
(±)- formation		 activation 231-233 7586124,
8901879,
9016811
CYP2C9 chemical haloalkane chloroform
(trichloromethane)		 dehalogenation reductive
(at high concentrations)		 activation 250 12584152
CYP2C9 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (low
Km, low activity, major
enzyme at low
concentrations); oxidation		 activation 101, 108,
251-254 		11377097,
19501186,
8242617,
9010702,
10348794,
10692561
CYP2C9 chemical PAH dibenz[a,h]anthracene 3,4-dihydrodiol formation activation 184 8638931
CYP2C9 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation (low
Km), oxidation (at high
concentration)		 activation 87, 259 20507880,
8242617
CYP2C9 natural
compound		 phenylpropene, from
Rhizoma
acorigraminei 		methyleugenol C1′-hydroxylation
(medium activity, high
Km), at high concentration		 activation 196, 199 15914212,
16411663
CYP2C19 chemical triazole 1-aminobenzotriazole (1-
ABT)		 oxidation activation 140 17584015
CYP2C19 natural
compound		 furanoterpene
produced in sweet
potatoes infected with
Fusarium solani;
pulmonary toxin,
alkylating		 4-ipomeanol oxidation (major enzyme) activation 173 15892579
CYP2C19 chemical haloalkane chloroform
(trichloromethane)		 dehalogenation reductive
(at high concentration);
oxidation (at high
concentration)		 activation 250 12584152
CYP2C19 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (low
Km, low activity);
oxidation		 activation 108, 251-
254 		19501186,
8242617,
9010702,
10348794,
10692561
CYP2C19 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation
stereoselective for (S)-
(minor reaction, high Km),
oxidation (at high
concentration)		 activation 87, 259,
253, 276 		20507880,
8242617,
10348794,
10534317
CYP2C19 chemical nitrosamine N-nitrosomethylbutylamine oxidation activation 134 11600130
CYP2C19 chemical nitrosamine N-nitrosomethylethylamine oxidation activation 134 11600130
CYP2C19 chemical nitrosamine N-nitrosopyrrolidine Cα-hydroxylation (2-OH-
tetrahydrofuran
formation)		 activation 132, 133 11774366,
12214673
CYP2D6 chemical triazole 1-aminobenzotriazole (1-
ABT)		 oxidation activation 140 17584015
CYP2D6 chemical nitrosamine 3-(N-
nitrosomethylamino) propiona
ldehyde		 oxidation activation 68 15725615
CYP2D6 chemical nitroarene 3-nitrobenzanthrone nitroreduction potent
activation		 80 12782579
CYP2D6 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 Cα-
hydroxylation,methylene		 activation 170 9163700
CYP2D6 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 Cα-hydroxylation, methyl
(keto alcohol formation),
high Km, medium activity,
or high activity, major
reaction and Cα-
methylene (keto aldehyde
formation), high Km, low
activity, minor reaction		 activation 170, 213-
216, 281 		9163700,
1312898,
7595636,
8806763,
10803680,
8485585
CYP2D6 natural
compound		 furanoterpene
produced in sweet
potatoes infected with
Fusarium solani;
pulmonary toxin,
alkylating		 4-ipomeanol oxidation activation 173 15892579
CYP2D6 chemical PAH 7,12-
dimethylbenz[a]anthracene		 oxidation activation 87 20507880
CYP2D6 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) oxidation activation 61 11377247
CYP2D6 chemical haloalkane chloroform
(trichloromethane)		 dehalogenation, reductive
(at high concentration)		 activation 250 12584152
CYP2D6 drug pyrido-carbazole;
antineoplastic,
alkaloid,
Apocyanaceae plant
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine oxidation N2-;
hydroxylation, C13- (low
activity)		 activation 39, 40, 187,
188 		16936898,
21753906,
15548707,
17197724
CYP2D6 drug oxazaphosporine;
anticancer, nitrogen
mustard		 alkylating
ifosfamide		 oxidation (at high
concentration)		 activation 87 20507880
CYP2E1 chemical haloalkane 1, 2-dibromoethane (ethylene
dibromide)		 oxidation to 2-
bromoacetaldehyde		 activation 107, 230,
180 		1486866,
8870687,
1664256
CYP2E1 chemical haloalkane 1, 2-dichloroethane (ethylene
dichloride)		 oxidation activation 107, 282 1486866,
1664256
CYP2E1 chemical haloalkane 1, 2-dichloropropane
(propylene dichloride)		 oxidation activation 107, 282 1486866,
1664256
CYP2E1 chemical hydrazine 1, 2-dimethylhydrazine oxidation activation 283 15576447
CYP2E1 chemical haloalkane 1,1,2-trichloroethane oxidation activation 284 8671747
CYP2E1 chemical haloalkene 1,1,3-trichloropropene oxidation activation 284 8671747
CYP2E1 chemical haloalkene 1,1-dichloroethylene
(vinylidene chloride)		 epoxidation activation 285 15319346
CYP2E1 chemical diene 1,3-butadiene butadiene monoxide
(epoxybutene) (S)- and
(R)- formation (high
activity, major enzyme)		 potent
activation		 231-233,
286 		7586124,
8901879,
9016811,
9635416
CYP2E1 chemical halobenzene 1,4-dichlorobenzene oxidation activation 287 9817075
CYP2E1 chemical triazole 1-aminobenzotriazole (1-
ABT)		 oxidation activation 140 17584015
CYP2E1 chemical haloalkane 2, 2-dichloro-1,1,1-
trifluoroethane (HCFC-123)		 oxidation activation 268, 269,
288, 289 		11684364,
11684365,
7975716,
8199305
CYP2E1 chemical halobenzene 2,3-dichlorobutane oxidation activation 284 8671747
CYP2E1 chemical nitrile, herbicide 2,6-dichlorobenzonitrile
(dichlobenil)		 epoxidation, C2,3- activation 234,235 8649351,
8863822
CYP2E1 chemical arylamine 2,6-dimethylaniline N-hydroxylation (at
higher concentration)		 activation 236 11409937
CYP2E1 chemical arylamine 2-aminoanthracene N-hydroxylation activation 61 11377247
CYP2E1 chemical arylamine 2-aminofluorene (2-AF) N-hydroxylation activation 61 11377247
CYP2E1 natural
compound		 furanoterpene
produced in sweet
potatoes infected with
Fusarium solani;
pulmonary toxin,
alkylating		 4-ipomeanol oxidation activation 173 15892579
CYP2E1 chemical unsaturated 4-vinyl-1-cyclohexene, (S)-
and (R)-		 epoxidation 7,8-,
stereoselective for (S)-;
epoxidation 1,2-,
stereoselective for (R)-		 activation 100, 273 11502734,
11159809
CYP2E1 chemical acrylic amide acrylamide epoxidation to
glycidamide		 activation 290, 291 19190172,
20209648
CYP2E1 chemical aliphatic nitrile acrylonitrile (vinyl cyanide,
cyanoethylene)		 oxidation (2-
cyanoethylene oxide
formation)		 activation 107, 282,
290 		1486866,
1664256,
8117926
CYP2E1 chemical oxidoazanium azoxymethane oxidation activation 283 15576447
CYP2E1 chemical aromatic hydrocarbon benzene hydroxylation, aromatic
(via benzene oxide,
muconic acid, and
benzoquinone formation,
major enzyme at low
concentrations)		 activation 107, 110,
282, 293-
295 		1486866,
7923572,
1664256,
10207612,
11083083,
15122651
CYP2E1 chemical aliphatic epoxide,
metabolite		 butadiene monoxide (1, 2-
epoxy-3-butene)		 diepoxybutane meso-
(major) and (±)-
formation, high activity,
major enzyme		 potent
activation		 231-233,
296 		7586124,
8901879,
9016811,
17298833
CYP2E1 chemical haloalkane carbon tetrachloride dechlorination reductive
(at low concentrations),
oxidative stress induction		 potent
activation		 106, 297-
300 		1486866,
8571359,
10731522,
8471158,
12235922
CYP2E1 chemical haloalkane chloroform
(trichloromethane)		 dehalogenation reductive
(at high concentration,
major enzyme); oxidation
(major enzyme at low
concentration)		 potent
activation		 66, 107,
252, 282,
299, 301 		9685642,
1486866,
12584152,
1664256,
8471158,
15129551
CYP2E1 chemical haloalkene chloroprene epoxidation activation 302 11397396
CYP2E1 drug platinum-containing;
anticancer		 cisplatin oxidation activation 303, 304 16251482,
17761302
CYP2E1 drug imidazole; anticancer,
alkylating		 dacarbazine N-demethylation activation 111 10473105
CYP2E1 chemical haloalkene
dichloromethane (methylene
chloride)		 dehalogenation oxidative activation 107, 282,
284, 297 		1486866,
1664256,
8671747,
8571359
CYP2E1 chemical organic solvents,
alcohol		 ethanol oxidation, reactive
oxygen species
production		 activation 305-309 7687464,
16052683,
16878272,
16356668,
21146245
CYP2E1 natural
compound		 carbamic acid
derivative;
fermentation by-
product		 ethyl carbamate (urethane) oxidation to vinyl
carbamate epoxide		 activation 107, 282,
310-312 		1486866,
1664256,
9344892,
9150748,
11181492
CYP2E1 chemical furan furan oxidation, cis-2-butene-
1,4-dial formation		 activation 313 16006568
CYP2E1 chemical organic solvents,
alkylformamide		 N, N-dimethylformamide(DMF) N-demethylation (high
activity)		 activation 314, 315 8477011,
11684354
CYP2E1 chemical organic solvents,
alkylformamide		 N-methylformamide oxidation
(methylisocyanate
formation)		 activation 316 1538706
CYP2E1 chemical nitrosamine N-nitrosodiethanolamine oxidation activation 317 18616954
CYP2E1 chemical nitrosamine N-nitrosodiethylamine
(N,N-
diethylnitrosamine,)		 oxidation (major enzyme) potent
activation		 107, 132-
134, 141-
144, 244,
318, 319 		1486866,
11774366,
12214673,
11600130,
15728263,
15843388,
17158518,
9860501,
10837014,
11733072,
14669323
CYP2E1 chemical nitrosamine N-nitrosodimethylamine
(N,N-dimethylnitrosamine,
DMN)		 oxidation (major enzyme) activation 107, 134,
170, 244,
246, 317,
318, 320,
321, 322 		1486866,
11600130,
9163700,
10837014,
1423839,
18616954,
11733072,
8692217,
10366544,
15668106
CYP2E1 chemical nitrosamine N-nitrosodi-n-propylamine
(N-nitrosodipropylamine)		 Cα-hydroxylation and N-
depropylation (major
enzyme); oxidation		 activation 134, 141-
143, 244,
318, 323-
325 		11600130,
15728263,
15843388,
17158518,
10837014,
11733072,
9247615,
8824531,
10910959
CYP2E1 chemical nitrosamine N-nitrosoethylbutylamine oxidation activation 134, 244 11600130,
10837014
CYP2E1 chemical nitrosamine N-nitrosomethylbutylamine oxidation potent
activation		 107, 134,
244 		1486866,
11600130,
10837014,
CYP2E1 chemical nitrosamine N-nitrosomethylethylamine oxidation potent
activation		 134, 244 11600130,
10837014
CYP2E1 chemical nitrosamine N-nitrosomethylpropylamine oxidation potent
activation		 134, 244 11600130,
10837014
CYP2E1 chemical nitrosamine N-nitrosomorpholine oxidation activation 132, 133,
326 		11774366,
12214673,
10461547
CYP2E1 chemical nitrosamine N-nitroso-N-
methylbenzylamine		 oxidation activation 107 1486866
CYP2E1 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 hydroxylation C5′- (lactol
formation, low activity)		 activation 134, 244,
247, 256,
257 		11600130,
10837014,
1423839,
9276639,
7646564
CYP2E1 chemical nitrosamine N-nitrosopyrrolidine Cα-hydroxylation (2-OH-
tetrahydrofuran
formation); oxidation		 activation 132-134,
244, 327 		11774366,
12214673,
11600130,
10837014,
17457417
CYP2E1 chemical o-methoxyaniline o-anisidine (2-
methoxyaniline)		 N-hydroxylation (major
enzyme in microsomal
model)		 potent
activation		 201, 328 15828049,
21217841
CYP2E1 chemical aromatic
hydrocarbons, alkyl
benzene		 styrene (vinyl benzene) oxidation, medium Km,
major enzyme in liver at
low concentration,
stereoselective		 activation 66, 107,
202-205,
280, 282,
329 		9685642,
1486866,
9253143,
7696548,
11407535,
12616646,
16125881,
1664256,
16872732
CYP2E1 chemical haloalkene tetrachloroethylene oxidation activation 284 8671747
CYP2E1 chemical haloalkene trichloroethylene (TCE) oxidation to
trichloroethylene oxide
and chloral hydrate form
ation (major enzyme)		 activation 107, 282,
330-333 		1486866,
1664256,
9070354,
10807551,
11304134,
15987776
CYP2E1 chemical vinyl halide vinyl bromide
(bromoethylene)		 oxidation activation 66, 107,
282 		9685642,
1486866,
1664256
CYP2E1 chemical carbamic acid
derivative, metabolite		 vinyl carbamate epoxide formation activation 66, 107,
282, 312 		9685642,
1486866,
1664256,
11181492
CYP2E1 chemical vinyl halide vinyl chloride
(chloroethylene)		 oxidation potent
activation		 66, 107,
282, 299 		9685642,
1486866,
1664256,
8471158
CYP2E1 chemical cyclohexane derivative vinylcyclohexane oxidation (epoxidation) activation 329 16872732
CYP2F1 natural
compound		 indole, alkylating,
pulmonary toxin;
present in higher
concentrations in
mammalian digestive
tract and coal tar		 3-methylindole, skatole dehydrogenation
(desaturation, 3-
methyleneindolenine
form., low Km, medium
activity, high efficiency),
major enzyme		 potent
activation		 75-78, 334,
335 		8558432,
11408359,
12563100,
20795680,
10383923,
17962375
CYP2F1 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 hydroxylation, α-methyl
(keto alcohol formation)		 activation 213-216 1312898,
7595636,
8806763,
10803680
CYP2F1 natural
compound		 furanoterpene
produced in sweet
potatoes infected with
Fusarium solani;
pulmonary toxin,
alkylating		 4-ipomeanol oxidation activation 172 1651809
CYP2F1 chemical PAH naphthalene oxidation activation 334 10383923
CYP2F1 chemical aromatic hydrocarbon,
alkyl benzene		 styrene (vinyl benzene) oxidation (major enzyme
in lung microsomes)		 activation 202-205,
278 		9253143,
7696548,
11407535,
12616646,
16125881
CYP2W1 chemical PAH, metabolite (±)-benzo[a]pyrene-7,8-diol oxidation activation 210 16551781
CYP2W1 chemical arylamine 2-aminoanthracene oxidation activation 210 16551781
CYP2W1 chemical arylamine 2-aminofluorene (2-AF) oxidation activation 210 16551781
CYP2W1 chemical heterocyclic amine 3-amino-1,4-dimethyl-5H-
pyrido[4,3-b]indole (Trp-P-1)		 oxidation activation 210 16551781
CYP2W1 chemical azoaromatic amine 3-methoxy-4-
aminoazobenzene		 oxidation activation 210 16551781
CYP2W1 chemical PAH, metabolite 5-methylchrysene-1,2-diol oxidation activation 210 16551781
CYP2W1 Natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) oxidation activation 210 16551781
CYP2W1 chemical PAH, metabolite chrysene-1,2-diol oxidation activation 210 16551781
CYP2W1 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 oxidation activation 210 16551781
CYP2W1 natural
compound		 furanoxanthone;
mycotoxin, produced
by Aspergillus species		 sterigmatocystin oxidation activation 210 16551781
CYP3A4 chemical nitroarene 1, 2-dihydro-1,2-dihydroxy-
6-nitrochrysene		 oxidation activation 219 8481905
CYP3A4 chemical nitroarene 6-nitrochrysene oxidation activation 12 2655891
CYP3A4 chemical nitroarene 1,6-dinitropyrene nitroreduction activation 174 10197616
CYP3A4 chemical triazole 1-aminobenzotriazole (1-
ABT)		 oxidation activation 140 17584015
CYP3A4 chemical arylamine, metabolite
of 1-nitropyrene		 1-aminopyrene oxidation activation 54 11525925
CYP3A4 chemical nitroarene 1-nitropyrene epoxidation C4,5-, minor
reaction		 activation 54, 107,
174 		11525925,
1486866,
10197616
CYP3A4 chemical arylamine 2-aminofluorene oxidation activation 61, 336 9328287,
11377247
CYP3A4 chemical nitroarene 3,6-dinitrobenzo[e]pyrene niroreduction and O-
acetylation		 activation 70 19393727
CYP3A4 chemical heterocyclic amine 3-amino-1,4-dimethyl-5H-
pyrido[4,3-b]indole (Trp-P-1)		 N-hydroxylation potent
activation		 12, 61 2655891,
11377247
CYP3A4 chemical heterocyclic amine 3-amino-1-methyl-5H-
pyrido[4,3-b]indole (Trp-P-2)		 N-hydroxylation potent
activation		 61 11377247
CYP3A4 chemical azoaromatic amine 3-methoxy-4-
aminoazobenzene		 oxidation activation 336 9328287
CYP3A4 chemical arylamine 4,4′-methylene bis(2-
chloroaniline) (MOCA)		 oxidation, N- (major
enzyme)		 activation 66, 107,
249 		9685642,
1486866,
1740010
CYP3A4 Natural
compound		 furanoterpene
produced in sweet
potatoes infected with
Fusarium solani;
pulmonary toxin,
alkylating		 4-ipomeanol epoxidation; oxidation,
minor enzyme		 activation 140, 172,
173 		17584015,
1651809,
15892579
CYP3A4 chemical nitroarene 4-nitropyrene 4-aminopyrene formation
(nitroreduction), major
enzyme		 activation 174 10197616
CYP3A4 chemical N-heterocyclic
aromatic hydrocarbon,
dibenzocarbazole		 5,9-
dimethyldibenzo[c,g]carbazol
e		 oxidation activation 337 21798277
CYP3A4 chemical arylamine 6-aminochrysene oxidation (high activity) potent
activation		 12, 84, 85,
107, 336,
338 		2655891,
8118930,
8330339,
1486866,
9328287,
9493761
CYP3A4 chemical arylamine, metabolite 6-aminochrysene-1,2-diol Diol epoxide formation;
oxidation		 activation 84, 85 8118930,
8330339
CYP3A4 chemical N-heterocyclic
aromatic hydrocarbon,
dibenzocarbazole		 7H-dibenzo[c,g]carbazole oxidation activation 337 21798277
CYP3A4 chemical PAH, aza-aromatic 7-methylbenz[c]acridine oxidation. potent
activation		 92 7866988
CYP3A4 chemical PAH, metabolite benzo[a]pyrene 7,8-diol oxidation activation 12 2655891
CYP3A4 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) epoxidation exo-C8,9-
(major activating
enzyme), oxidation		 activation 11, 12, 42,
57, 61,
175-180,
182, 336,
339-341 		2492107,
2655891,
7955101,
15279838,
11377247,
2162057,
7766804,
8261428,
12079611,
1902334,
11782366,
16608170,
9328287,
1643250,
7545582,
7850790
CYP3A4 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin G1 (AFG1) oxidation activation 11, 12, 107,
148, 341-
343 		2492107,
2655891,
1486866,
8082563,
7850790,
352361,
12849689
CYP3A4 chemical herbicide,
chloroacetamide		 alachlor oxidation activation 274 11133395
CYP3A4 chemical herbicide,
chloroacetamide		 butachlor oxidation activation 274 11133395
CYP3A4 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation;
oxidation		 activation 108, 251-
254, 275,
344 		19501186,
8242617,
9010702,
10348794,
10692561,
9923542,
15919850
CYP3A4 chemical PAH), aza-aromatic dibenz[a,j]acridine 3,4-dihydrodiol formation potent
activation		 92 7866988
CYP3A4 drug pyrido-carbazole;
antineoplastic,
alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine hydroxylation, C13-
(major enzyme) and C12-
(minor reaction);
oxidation N2- (major
enzyme		 potent
activation		 39, 40,
287-290,
345 		16936898,
21753906,
11755121,
12123750,
15548707,
17197724,
20576524
CYP3A4 physiologi
cal
compound		 estrogen 17β-estradiol C2-hydroxylation (major
reaction, major enzyme,
medium Km, medium
efficiency, high activity),
major metabolite and
major enzyme in liver;
oxidation, 2,3-quinone
formation (lower
activity); C4-
hydroxylation (minor
reaction, major enzyme,
medium Km, medium
activity, medium
efficiency); oxidation,
3,4-quinone formation;
C16α-hydroxylation (high
Km, low activity)		 activation 107, 122-
124, 126-
130, 190-
193, 346,
347 		1486866,
9625734,
9054608,
9667077,
11555828,
12865317,
15784278,
16112414,
17570247,
1449532,
9635876,
11454902,
11741520,
10821664,
12124305
CYP3A4 physiologi
cal
compound		 estrogen estrone C2-hydroxylation (high
Km, major metabolite, low
activity); oxidation, 2,3-
quinone formation; C4-
hydroxylation (high Km,
low activity, major
enzyme); C16α-
hydroxylation (high Km,
low activity, major
enzyme)		 activation 48, 122-
124, 127,
128, 130,
191, 192 		10426814,
9625734,
9054608,
9667077,
12865317,
15784278,
17570247,
9635876,
11454902
CYP3A4 drug estradiol derivative;
estrogen,
contraceptive		 17α-ethynylestradiol (ethi-
nylestradiol 17α-)		 oxygenation (2-
hydroxylation, 17α-
inactivation)		 activation 140, 348 17584015,
17251390
CYP3A4 drug antimitotic,
epipodophyllotoxin,
topoisomerase II
inhibitor		 etoposide (VP-16) O-demethylation
(catechol formation), high
Km, high activity, major
enzyme		 activation 349-351 8114683,
9456308,
17168690
CYP3A4 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation
stereoselective for (R)-
(high Km, high activity),
oxidation at high
concentrations		 potent
activation		 87, 251,
254, 275-
277, 344,
352-355 		20507880,
8242617,
10692561,
15919850,
10534317,
15821045,
9923542,
8161344,
10101149,
10348794,
16854777
CYP3A4 chemical herbicide,
chloroacetamide		 metolachlor oxidation activation 274 11133395
CYP3A4 natural
compound		 alkaloid, pyrrolizidine,
genotoxic		 monocrotaline dehydrogenation activation 356 15649625
CYP3A4 chemical aziridine N, N’, N”-triethylene
thiophosphoramide
(thioTEPA)		 desulfuration, TEPA
formation (minor enzyme)		 activation 279 12107550
CYP3A4 chemical tobacco-specific
nitrosamine		 N’-nitrosoanabasine oxidation (major enzyme) activation 132, 133 11774366,
12214673
CYP3A4 chemical nitrosamine N-nitrosodibutylamine (N,N-
dibutylnitrosamine)		 oxidation activation 134 11600130
CYP3A4 chemical nitrosamine N-nitrosodiethylamine (N,N-diethylnitrosamine) oxidation activation 134, 255 11600130,
1423839
CYP3A4 chemical nitrosamine N-nitrosoethylbutylamine oxidation activation 134 11600130
CYP3A4 chemical nitrosamine N-nitrosomethylbutylamine oxidation activation 134 11600130
CYP3A4 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-nitrosonornicotine, NNN) hydroxylation C2′- (keto
alcohol formation);
oxidation		 activation 132, 133,
264, 265 		11774366,
12214673,
9276639,
7646564
CYP3A4 chemical nitrosamine N-nitrosopiperidine Cα-hydroxylation (2-OH-
tetrahydropyran and 2-
OH-5-
methyltetrahydrofuran
formation); oxidation		 activation 132, 133 11774366,
12214673
CYP3A4 chemical nitrosamine N-nitrosopyrrolidine Cα-hydroxylation (2-OH-
tetrahydrofuran
formation); oxidation		 activation 132, 133 11774366,
12214673
CYP3A4 natural
compound		 pyrrolizidine alkaloid
from Senecio retrorsus 		retrorsine dehydrogenation activation 356 15649625
CYP3A4 natural
compound		 pyrrolizidine alkaloid,
food contaminant
(meat, milk, and
honey)		 riddelline dehydrogenation activation 356 15649625
CYP3A4 natural
compound		 pyrrolizidine alkaloid,
genotoxic		 senecionine dehydrogenation activation 107, 357 1486866,
2009596
CYP3A4 natural
compound		 furanoxanthone;
mycotoxin, produced
by Aspergillus species		 sterigmatocystin oxidation activation 11, 12, 66,
107, 336,
341 		2492107,
2655891,
9685642,
1486866,
9328287,
7850790
CYP3A4 drug triphenylethyleneamin
e; antiestrogen,
estrogen receptor
modulator		 tamoxifen Cα-hydroxylation (major
enzyme), catechol
formation, oxidation, at
high concentrations		 activation 87, 354,
358-364 		20507880,
10348797,
12018981,
12971802,
14678348,
15159443,
16533026,
12124303,
12419838
CYP3A4 chemical organophosphate tris(2,3-
dibromopropyl)phosphate		 oxidation activation 12, 107 2655891,
1486866
CYP3A5 chemical PAH, aza-aromatic 7-methylbenz[c]acridine oxidation potent
activation		 92 7866988
CYP3A5 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) epoxidation exo-8,9-
(major reaction);
oxidation		 activation 182, 365 16608170,
7893152
CYP3A5 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (very
low activity) activation to
cytotoxic metabolites		 activation 253 10348794
CYP3A5 chemical PAH, aza-aromatic dibenz[a,j]acridine 3,4-dihydrodiol formation activation 92 7866988
CYP3A5 physiologi
cal
compound		 estrogen 17β-estradiol C2-hydroxylation; C4-
hydroxylation (major
reaction); C16α-
hydroxylation (low
activity)		 activation 127, 128,
191, 192,
347 		12865317,
15784278,
9635876,
11454902,
12124305
CYP3A5 drug estradiol derivative;
estrogen,
contraceptive		 17α-ethynylestradiol
(ethinylestradiol, 17α-)		 oxygenation (2-
hydroxylation, 17α-
mechanism-based
inactivation)		 activation 140, 348 17584015,
17251390
CYP3A5 drug antimitotic,
epipodophyllotoxin,
topoisomerase II
inhibitor		 etoposide (VP-16) O-demethylation
(catechol formation),
medium Km, high activity,
minor enzyme		 activation 349 8114683
CYP3A5 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation,
stereoselective for (R)-		 activation 253, 276,
277, 353,
355 		10348794,
10534317,
15821045,
10101149,
16854777
CYP3A5 chemical tobacco-specific
nitrosamine		 N’-nitrosoanabasine oxidation activation 132, 133 11774366,
12214673
CYP3A5 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 oxidation activation 132, 133 11774366,
12214673
CYP3A7 chemical arylamine 2-aminofluorene (2-AF) oxidation activation 336 9328287
CYP3A7 chemical azoaromatic amine 3-methoxy-4-
aminoazobenzene		 oxidation activation 336 9328287
CYP3A7 chemical arylamine 6-aminochrysene oxidation activation 336, 338 9328287,
9493761
CYP3A7 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) epoxidation exo-C8,9-;
oxidation		 activation 107, 182,
336, 338,
341, 366 		1486866,
16608170,
9328287,
9493761,
7850790,
9044840
CYP3A7 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin G1 (AFG1) oxidation activation 341 7850790
CYP3A7 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation activation 253, 275 10348794,
15919850
CYP3A7 physiologi
cal
compound		 estrogen 17β-estradiol C2-hydroxylation
(medium Km, low activity,
major reaction); C4-
hydroxylation (low
activity, high Km); C16α-
hydroxylation (very low
activity, high Km)		 activation 127, 128,
347 		12865317,
15784278,
12124305,
CYP3A7 physiologi
cal
compound		 estrogen estrone C2-hydroxylation
(medium Km, medium
activity); C4-
hydroxylation (low
activity, medium Km);
C16α-hydroxylation
(medium Km, medium
activity)		 activation 127, 128 12865317,
15784278
CYP3A7 drug oxazaphosporine;
anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation
stereoselective for (R)-
(high Km, medium (S-)
and high (R-) activity,
minor enzyme and
reaction)		 activation 253, 273 10348794,
15919850
CYP3A7 natural
compound		 furanoxanthone;
mycotoxin, produced
by Aspergillus species		 sterigmatocystin oxidation activation 336, 338,
341 		9328287,
9493761,
7850790
CYP4B1 chemical arylamine 2-aminofluorene (2-AF) N-hydroxylation;
oxidation		 activation 367, 368 11396967,
11062028
CYP4B1 natural
compound		 furanoterpene
produced in sweet
potatoes infected with
Fusarium solani;
pulmonary toxin,
alkylating		 4-ipomeanol oxidation activation 172 1651809
CYP4B1 chemical aromatic hydrocarbon benzene oxidation (at high conc.,
minor reaction)		 activation 294 11083083
CYP19A1
(aromatase) 		physiologi
cal
compound		 estrogen 17β-estradiol C2-hydroxylation
(medium Km)		 activation 125, 369 8930523,
8476762
CYP19A1
(aromatase) 		physiologi
cal
compound		 estrogen estrone C2-hydroxylation
(medium Km)		 activation 125, 369 8930523,
8476762
Epoxide
hydrolase,
EH 		chemical PAH, metabolite benzo[a]pyrene-7,8-oxide hydrolysis to
benzo[a]pyrene -7,8-diol		 activation 51, 220 21028851,
10409402
FMO1 chemical thiocarbamide thiourea S-oxidation (medium Km,
high activity)		 activation 370, 371 10901713,
14976351
FMO2 chemical thiocarbamide 1-phenylthiourea S-oxidation activation 372 15144220
FMO2 chemical thiocarbamide α-naphthylthiourea S-oxidation activation 372 15144220
FMO2 chemical thiocarbamide ethylenethiourea S-oxidation activation 372 15144220
FMO2 chemical thiocarbamide thiourea S-oxidation (medium Km,
high activity)		 activation 372, 373 15144220,
11744609
FMO3 chemical thiocarbamide thiourea S-oxidation (medium Km,
high activity)		 activation 374 12093470
GST chemical haloalkane 1, 2-dibromoethane (ethylene
dibromide)		 GSH conjugation activation 375-378 8330352,
16948056,
12542971,
15554237
GST chemical haloalkane 1, 2-dichloroethane, ethylene
dichloride		 GSH conjugation activation 375, 378 8330352,
15554237
GST chemical haloalkene chlorotrifluoroethene GSH conjugation activation 378 15554237
GST chemical haloalkane dichloromethane, methylene
chloride		 GSH conjugation activation 284, 377,
378 		8671747,
12542971,
15554237
GST chemical haloalkene hexachlorobutadiene GSH conjugation activation 378 15554237
GST chemical haloalkene tetrafluoroethene GSH conjugation activation 378 15554237
GST chemical haloalkene trichloroethene GSH conjugation activation 378 15554237
GST T1-1 chemical haloalkane 1, 2-dibromoethane (ethylene
dibromide)		 GSH conjugation activation 378 8565128
GST T1-1 chemical haloalkane dibromomethane (methylene
dibromide)		 GSH conjugation activation 378 8565128
GST T1-1 chemical haloalkane diepoxybutane (butadiene
diepoxide)		 GSH conjugation activation 379, 380 8565128,
222181695
GST A1-1 chemical haloalkane diepoxybutane, butadiene
diepoxide		 GSH conjugation activation 380 222181695
GST A3-3 chemical haloalkane diepoxybutane (butadiene
diepoxide)		 GSH conjugation activation 380 222181695
GST M1-1 chemical haloalkane diepoxybutane (butadiene
diepoxide)		 GSH conjugation activation 380 222181695
GST P1-1 chemical haloalkane diepoxybutane (butadiene
diepoxide)		 GSH conjugation activation 380 222181695
Lactoperoxi
dase (LPO) 		chemical arylamine, metabolite 3-aminobenzanthrone N-oxidation activation 72, 73 15885895,
16601755
Lactoperoxi
dase (LPO) 		drug pyrido-carbazole;
antineoplastic,
alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor and DNA
binding		 Ellipticine oxidation activation 39, 40 16936898,
21753906
Myeloperoxi
dase (MPO) 		chemical arylamine, metabolite 3-aminobenzanthrone N-oxidation activation 72, 73 15885895,
16601755
Myeloperoxi
dase (MPO) 		drug pyrido-carbazole;
antineoplastic,
alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine oxidation activation 39, 40 16936898,
21753906
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 1,2-dibromoethane (ethylene
dibromide)		 conjugation activation 381, 382 12151404,
15257623
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 dibromomethane (methylene
dibromide)		 conjugation activation 382, 383 15257623,
15206895
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 bromomethyl acetate conjugation activation 383 15206895
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 dichloromethane (methylene
dichloride)		 conjugation activation 382 15257623
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 bromochloromethane conjugation activation 382 15257623
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 1,2-diiodoethane (ethylene
diiodide)		 conjugation activation 382 15257623
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 1,2-bromochloroethane conjugation activation 382 15257623
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 1,3-dibromopropane conjugation activation 382 15257623
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 1,4-dibromobutane conjugation activation 382 15257623
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 1,3-diiodopropane conjugation activation 382 15257623
O6-
alkylguanine
DNA alkyl
transferase
(MGMT) 		chemical bifunctional
electrophile		 diepoxybutane (butadiene
diepoxide)		 conjugation activation 382 15257623
NADPH-
cytochrome
P450
reductase
(POR) 		chemical nitroarene 1,8-dinitropyrene nitroreduction activation 53, 384 11113705,
15606153
NADPH-
cytochrome
P450
reductase
(POR) 		chemical nitroarene 1-nitro-6-nitrosopyrene reduction activation 384 15606153
NADPH-
cytochrome
P450
reductase
(POR) 		chemical nitroarene 1-nitro-8-nitrosopyrene reduction activation 384 15606153
NADPH-
cytochrome
P450
reductase
(POR) 		chemical nitroarene 3,6-dinitrobenzo[e]pyrene niroreduction and O-
acetylation		 activation 70 19393727
NADPH-
cytochrome
P450
reductase
(POR) 		chemical nitroarene 3-nitrobenzanthrone nitroreduction activation 80 12782579
NADPH-
cytochrome
P450
reductase
(POR) 		chemical quinone anthraquinone reduction activation 385 11697035
NADPH-
cytochrome
P450
reductase
(POR) 		drug dihydroxyanthraquino
ne; laxative		 danthron reduction activation 383 11697035
Xanthine
oxidoreducta
se (XOR) 		chemical nitroarene 2-nitroanisole nitroreduction to
hydroxylamine		 activation 328 21217841
Xanthine
oxidoreducta
se (XOR) 		chemical nitroarene 3-nitrobenzanthrone nitroreduction to
hydroxylamine		 activation 79 12740904
NAT1 chemical nitroarene 1,8-dinitropyrene O-acetylaton after
nitroreduction		 activation 386 10357791
NAT1 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-
(diallylamino)-5-
methoxyphenyl]-5-amino-7-
bromo-4-chloro-2H-benzotriazole (PBTA-8)		 O-acetylation activation 55 18562244
NAT1 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-
(diethylamino)-5-
methoxyphenyl]-5-amino-7-
bromo-4-chloro-2H-
benzotriazole (PBTA-7)		 O-acetylation activation 55 18562244
NAT1 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-[bis(2-
hydroxyethyl)amino]-5-
methoxyphenyl]-5-amino-7-
bromo-4-chloro-2H-
benzotriazole (PBTA-6)		 O-acetylation activation 55 18562244
NAT1 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-amino-
5-methoxyphenyl]-5-amino-
7-bromo-4-chloro-2H-
benzotriazole (PBTA-4)		 O-acetylation activation 55 18562244
NAT1 chemical arylamine, metabolite 2-acetylaminofluorene (2-
AAF)		 O-acetylation after N-hydroxylation potent
activation		 147 15450435
NAT1 chemical heterocyclic amine 2-amino-6-
methyldipyrido[1,2-a:3′,2′-d]-
imidazole (Glu-P-1)		 O-acetylation after N-
hydroxylation		 activation 386 10357791
NAT1 chemical arylamine 2-aminofluorene (2-AF) O-acetylaton after N-
hydroxylation		 activation 386, 387 10357791,
1617672
NAT1 chemical arylamine 2-naphthylamine O-acetylation after N-
hydroxylation		 activation 147 15450435
NAT1 chemical nitroaromatic 2-nitrofluorene O-acetylaton after
nitroreduction		 activation 386 10357791
NAT1 chemical nitroarene 3-acetylaminobenzanthrone O-acetylation after N-
hydroxylation, at higher
conc.		 potent
activation		 79 12740904
NAT1 chemical arylamine, metabolite 3-aminobenzanthrone O-acetylation after N-
hydroxylation, at higher
conccentrations		 potent
activation		 79 12740904
NAT1 chemical nitroarene 3-nitrobenzanthrone O-acetylation after nitro-
reduction to
hydroxylamine, at higher
concentrations		 potent
activation		 73, 79, 388 16601755,
12740904,
12419844
NAT1 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl
(4-ABP)		 O-acetylation after N-
hydroxylation		 potent
activation		 147, 389 15450435,
8353847
NAT1 chemical arylamine,
heterocyclic		 aminophenylnorharman O-acetylation after N-
hydroxylation		 activation 95 17067997
NAT1 chemical arylamine benzidine O-acetylation after N-
hydroxylation		 activation 147, 387 15450435,
1617672
NAT1 chemical arylamine, metabolite N-acetyl-N-hydroxy-3-
aminobenzanthrone		 O-acetylation at higher
concentrations		 potent
activation		 79, 387 12740904,
12419844
NAT1 chemical arylamine, tobacco
smoke compound,
metabolite		 N-hydroxy-4-aminobiphenyl
(N-OH-4-ABP)		 O-acetylation activation 389 8353847
NAT1 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-2-aminofluorene
(N-OH-2-AF)		 O-acetylation activation 389 8353847
NAT1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-
aminomethylphenylnorharma
n		 O-acetylation activation 95 17067997
NAT1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-
aminophenylnorharman		 O-acetylation activation 95 17067997
NAT1 chemical nitroarene nitrofen O-acetylation after
nitroreduction		 activation 390 14754874
NAT1 chemical o-methoxyaniline o-anisidine, 2-
methoxyaniline		 O-acetylation after N-
hydroxylation		 activation 147 15450435
NAT2 chemical nitroarene 1,8-dinitropyrene O-acetylaton after
nitroreduction		 potent
activation		 386 10357791
NAT2 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-
(diallylamino)-5-
methoxyphenyl]-5-amino-7-
bromo-4-chloro-2Hbenzotriazole
(PBTA-8)		 oxidation activation 55 18562244
NAT2 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-
(diethylamino)-5-
methoxyphenyl]-5-amino-7-
bromo-4-chloro-2Hbenzotriazole
(PBTA-7)		 oxidation activation 55 18562244
NAT2 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-[bis(2-
hydroxyethyl)amino]-5-
methoxyphenyl]-5-amino-7-
bromo-4-chloro-2H-
benzotriazole (PBTA-6)		 oxidation activation 55 18562244
NAT2 chemical 2-phenylbenzotriazole 2-[2-(acetylamino)-4-amino-
5-methoxyphenyl]-5-amino-
7-bromo-4-chloro-2H-
benzotriazole (PBTA-4)		 oxidation activation 55 18562244
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 2-amino-3,4-
dimethylimidazo[4,5-
f]quinolone (MeIQ)		 O-acetylation after N-
hydroxylation		 activation 386, 387 10357791,
1617672
NAT2 chemical heterocyclic amine 2-amino-6-
methyldipyrido[1,2-a:3′,2′-d]-
imidazole (Glu-P-1)		 O-acetylation after N-
hydroxylation		 activation 386 10357791
NAT2 chemical nitroarene 2-nitrobenzanthrone O-acetylation after
reduction to
hydroxylamine		 activation 391 17483118
NAT2 chemical nitroarene 3-acetylaminobenzanthrone O-acetylation after Nhydroxylation,
at higher
concentration		 potent
activation		 79 12740904
NAT2 chemical arylamine, metabolite 3-aminobenzanthrone O-acetylation after Nhydroxylation,
at higher
concentration		 potent
activation		 79 12740904
NAT2 chemical nitroarene 3-nitrobenzanthrone O-acetylation after nitro-
reduction to
hydroxylamine, at higher
concentration		 potent
activation		 73, 79, 388,
391		 16601755,
12740904,
12419844,
17483118
NAT2 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl
(4-ABP)		 O-acetylation after N-
hydroxylation		 activation 147, 389 15450435,
8353847
NAT2 chemical arylamine 6-aminochrysene O-acetylation after N-
hydroxylation		 activation 386 10357791
NAT2 chemical arylamine,
heterocyclic		 aminomethylphenylnorharma
n		 O-acetylation after N-hydroxylation activation 95 17067997
NAT2 chemical arylamine,
heterocyclic		 aminophenylharman O-acetylation after N-hydroxylation activation 95 17067997
NAT2 chemical arylamine,
heterocyclic		 aminophenylnorharman O-acetylation after N-
hydroxylation		 activation 95 17067997
NAT2 chemical arylamine, metabolite N-acetyl-N-hydroxy-3-
aminobenzanthrone		 O-acetylation at higher
conc.		 potent
activation		 79, 388 12740904,
12419844
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methylimidazo[4,5-
f]quinolone (N-hydroxyisoIQ)		 O-acetylation activation 392 7697826
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-3,4-
dimethylimidazo[4,5-
f]quinolone (N-hydroxy-
MeIQ)		 O-acetylation activation 392 7697826
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (N-hydroxy-
MeIQx)		 O-acetylation activation 392 7697826
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-3-
methylimidazo[4,5-
f]quinolone (N-hydroxy-IQ)		 O-acetylation potent
activation		 392, 393 7697826,
12067565
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-6-
methyldipyrido[1,2-a:3′,2′-d]-
imidazole (N-hydroxy-Glu-P-
1)		 O-acetylation activation 392 7697826
NAT2 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-2-
aminobenzanthrone		 O-acetylation activation 391 17483118
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-
aminodipyrido[1,2-a:3,2′-d]-
imidazole (N-hydroxy-Glu-P-
2)		 O-acetylation ativation 392 7697826
NAT2 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-3-
aminobenzanthrone		 O-acetylation activation 391 17483118
NAT2 chemical arylamine, tobacco
smoke compound,
metabolite		 N-hydroxy-4-aminobiphenyl
(N-OH-4-ABP)		 O-acetylation activation 389 8353847
NAT2 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxyaminofluorene
(N-OH-2-AF)		 O-acetylation activation 389 8353847
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-
hydroxyaminomethylphenyln
orharman		 O-acetylation activation 95 17067997
NAT2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-
hydroxyaminophenylnorharm
an		 O-acetylation activation 95 17067997
NAT2 chemical o-methoxyaniline o-anisidine, 2-
methoxyaniline		 O-acetylation after N-
hydroxylation		 activation 147 15450435
Prostaglandi
n H synthase
(PHS, COX) 		chemical arylamine, metabolite 3-aminobenzanthrone N-oxidation activation 72, 73 15885895,
16601755
Quinone
oxidoreducta
se (NQO1) 		chemical nitroarene 3-nitrobenzanthrone nitroreduction (major
enzyme)		 potent
activation		 73, 80 16601755,
12782579
SULT1A1 chemical PAH, metabolite (−)-1-hydroxyethylpyrene O-sulfonation activation 169, 394 10720750,
11535246
SULT1A1 chemical PAH, metabolite 1-(1-pyrenyl)ethanol O-sulfonation activation 395 9141497
SULT1A1 chemical PAH, metabolite 1-hydroxymethylpyrene O-sulfonation potent
activation		 169, 390,
396, 397 		10720750,
14754874,
10657971,
17936463
SULT1A1 natural
compound		 1-methoxy-3-
indolylmethyl
glucosinolate
breakdown product, in
many Brassica
vegetables		 1-methoxy-3-indolylmethyl-
alcohol		 O-sulfonation activation 398 20846518
SULT1A1 chemical benzylic alcohol,
nitroatromatic		 2,4-dinitrobenzylalcohol O-sulfonation activation 169, 394,
399 		10720750,
11535246,
11154739
SULT1A1 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 O-sulfonation after
oxidation		 activation 400 22006426
SULT1A1 chemical heterocyclic amine 2-amino-6-
methyldipyrido[1,2-a:3′,2′-d]-
imidazole (Glu-P-1)		 O-sulfonation after N-
hydroxylation		 potent
activation		 401 22072630
SULT1A1 chemical benzylic alcohol 2-aminobenzylalcohol O-sulfonation activation 3979 11154739
SULT1A1 chemical arylamine,
heterocyclic		 2-hydroxylamino-3-methyl-
9H-pyrido[2,3-b]indole (N-
OH-MeAαC)		 O-sulfonation potent
activation		 160 14729582
SULT1A1 chemical hydroxylamine,
heterocyclic		 2-hydroxylamino-5-
phenylpyridine		 O-sulfonation activation 394 11535246
SULT1A1 chemical nitroarene 2-nitrobenzanthrone O-sulfonation after
reduction to
hydroxylamine		 activation 391 17483118
SULT1A1 chemical nitroarene 3,9-dinitrofluoranthene O-sulfonation potent
activation		 401 22072630
SULT1A1 chemical nitroarene 3-acetylaminobenzanthrone O-sulfonation after N-
hydroxylation, at higher
concentrations		 potent
activation		 79 12740904
SULT1A1 chemical arylamine, metabolite 3-aminobenzanthrone O-sulfonation after N-
hydroxylation, at higher
concentrations		 potent
activation		 79 12740904
SULT1A1 chemical azoaromatic amine 3-methoxy-4-
aminoazobenzene		 O-sulfonation potent
activation		 401 22072630
SULT1A1 chemical nitroarene 3-nitrobenzanthrone O-sulfonation after
nitroreduction to
hydroxylamine		 potent
activation		 73, 79, 364,
391, 401 		16601755,
12740904,
12419844,
17483118,
22072630
SULT1A1 drug triphenylethyleneamin
e; antiestrogen,
estrogen receptor
modulator, metabolite		 4-hydroxytamoxifen O-sulfonation activation 402, 403 12034366,
21537383
SULT1A1 chemical furaldehyde derivative 5-hydroxymethylfurfural O-sulfonation activation 322, 397,
400 		15668106,
17936463,
22006426
SULT1A1 chemical nitroaromatic 5-nitroacenaphthene O-sulfonation potent
activation		 401 22072630
SULT1A1 chemical PAH, metabolite 7-hydroxy-7,8,9,10-
tetrahydrobenzo[a]pyrene		 O-sulfonation activation 395 9141497
SULT1A1 natural
compound		 nephrotoxin,
Aristolochia fangchi
compound, nitroarene		 aristolochic acids I and II O-sulfonation after
nitroreduction to
hydroxylamine		 potent
activation		 404 16161050
SULT1A1 chemical furan furan O-sulfonation after
oxidation		 activation 322 15668106
SULT1A1 chemical furan derivative furfuryl alcohol O-sulfonation activation 405 21729924
SULT1A1 chemical arylamine, metabolite N-acetyl-N-hydroxy-3-
aminobenzanthrone		 O-sulfonation, at higher
concentrations		 potent
activation		 79, 364 12740904,
12419844
SULT1A1 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-acetylamino-3-
methyl-5-phenylpyridine		 O-sulfonation activation 399 11154739
SULT1A1 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene
(N-OH-2-AAF)		 O-sulfonation activation 169, 406 10720750,
11535243
SULT1A1 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-acetylaminol-5-
phenylpyridine		 O-sulfonation activation 399 11154739
SULT1A1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-hydroxy-PhIP)		 O-sulfonation potent
activation		 393, 399 12067565,
11154739
SULT1A1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-3-
methylimidazo[4,5-
f]quinolone (N-hydroxy-IQ)		 O-sulfonation potent
activation		 407 16708048
SULT1A1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-6-
methyldipyrido[1,2-a:3′,2′-d]-
imidazole (N-hydroxy-Glu-P-
1)		 O-sulfonation activation 408 7834621
SULT1A1 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-2-
aminobenzanthrone		 O-sulfonation activation 401 17483118
SULT1A1 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-3-
aminobenzanthrone		 O-sulfonation activation 391 17483118
SULT1A1 chemical arylamine, tobacco
smoke compound,
metabolite		 N-hydroxy-4-aminobiphenyl
(N-OH-4-ABP)		 O-sulfonation activation 409 7859374
SULT1A1 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-2-aminofluorene
(N-OH-4-AF)		 O-sulfonation activation 408 7834621
SULT1A1 chemical nitroarene nitrofen O-sulfonation after
nitroreduction to
hydroxylamine		 potent
activation		 322, 390 15668106,
14754874
SULT1A1 chemical nitrosamine N-nitrosodimethylamine (N,
N-dimethylnitrosamine,
DMN)		 O-sulfonation after
oxidation		 activation 322 15668106
SULT1A1 chemical heterocyclic amine N-OH-4,4′-methylenebis(2-
chloroaniline) (N-OHMOCA)		 O-sulfonation activation 408 7834621
SULT1A2 chemical PAH, metabolite (−)-1-hydroxyethylpyrene O-sulfonation activation 394 11535246
SULT1A2 chemical PAH, metabolite 1-hydroxymethylpyrene O-sulfonation activation 394, 410 11535246,
12464797
SULT1A2 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 O-sulfonation after
oxidation		 activation 400 22006426
SULT1A2 chemical arylamine,
heterocyclic		 2-hydroxylamino-3-methyl-
9H-pyrido[2,3-b]indole (N-
OH-MeAαC)		 O-sulfonation activation 159 14729582
SULT1A2 chemical hydroxylamine,
heterocyclic		 2-hydroxylamino-5-
phenylpyridine		 O-sulfonation potent
activation		 394, 410 11535246,
12464797
SULT1A2 chemical nitroarene 3-acetylaminobenzanthrone O-sulfonation after N-
hydroxylation, at higher
concentrations		 potent
activation		 79 12740904
SULT1A2 chemical arylamine, metabolite 3-aminobenzanthrone O-sulfonation after N-
hydroxylation, at higher
concentrations		 potent
activation		 79 12740904
SULT1A2 chemical nitroarene 3-nitrobenzanthrone O-sulfonation after
nitroreduction to
hydroxylamine		 activation 73, 79 16601755,
12740904
SULT1A2 chemical furaldehyde derivative 5-hydroxymethylfurfural O-sulfonation activation 400 22006426
SULT1A2 chemical arylamine, metabolite N-acetyl-N-hydroxy-3-
aminobenzanthrone		 O-sulfonation, at higher
concentrations		 potent
activation		 79, 388 12740904,
12419844
SULT1A2 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-acetylamino-3-
methyl-5-phenylpyridine		 O-sulfonation activation 399 11154739
SULT1A2 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene (N-OH-
2-AAF)		 O-sulfonation potent
activation		 169, 394,
410 		10720750,
11535246,
12464797
SULT1A2 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-acetylaminol-5-
phenylpyridine		 O-sulfonation activation 399 11154739
SULT1A2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 O-sulfonation potent
activation		 393, 399 12067565,
11154739
SULT1A2 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-2-aminofluorene
(N-OH-2-AF)		 O-sulfonation potent
activation		 401 22072630
SULT1A3 natural
compound		 alkenylbenzene;
occurs in a variety of
foods including
essential oils of
tarragon, sweet basil,
sweet fennel, anis,
metabolite		 1′-hydroxyestragole O-sulfonation activation 197, 401 21459083,
22072630
SULT1A3 chemical PAH, metabolite 1-hydroxymethylpyrene O-sulfonation activation 169, 394,
396 		10720750,
11535246,
10657971
SULT1A3 chemical nitroalkane 2-nitropropane O-sulfonation, propane 2-
nitronate formation		 activation 169, 396 1072075,
10657971
SULT1A3 natural
compound		 alkenylbenzene;
occurs in a variety of
foods including
essential oils of
tarragon, sweet basil,
sweet fennel, anis		 estragole O-sulfonation after C1′-
hydroxylation		 activation 401 22072630
SULT1A3 chemical nitroarene nitrofen O-sulfonation after
nitroreduction to
hydroxylamine		 activation 390 14754874
SULT1B1 chemical PAH, aldehyde 1-formylpyrene O-sulfonation activation 399 11154739
SULT1B1 chemical PAH, metabolite 1-hydroxymethylpyrene O-sulfonation activation 394 11535246
SULT1B1 chemical arylamine,
heterocyclic		 2-hydroxylamino-3-methyl-
9H-pyrido[2,3-b]indole (N-
OH-MeAαC)		 O-sulfonation activation 159 14729582
SULT1B1 chemical hydroxylamine,
heterocyclic		 2-hydroxylamino-5-
phenylpyridine		 O-sulfonation activation 394 11535246
SULT1B1 chemical PAH, metabolite 4-
hydroxycyclopenta[d,e.f]chry
sene		 O-sulfonation potent
activation		 169, 394 10720750,
11535246
SULT1B1 chemical PAH, metabolite 6-
hydroxymethylbenzo[a]pyren
e		 O-sulfonation potent
activation		 394 11535246
SULT1B1 natural
compound		 nephrotoxin,
Aristolochia fangchi
compound, nitroarene		 aristolochic acids I and II O-sulfonation after
nitroreduction to
hydroxylamine		 activation 394 16161050
SULT1C1 chemical PAH, metabolite (−)-1-hydroxyethylpyrene O-sulfonation activation 392 11535246
SULT1C1 chemical arylamine,
heterocyclic		 2-hydroxylamino-3-methyl-
9H-pyrido[2,3-b]indole (N-
OH-MeAαC)		 O-sulfonation activation 169 14729582
SULT1C1 chemical nitroarene nitrofen O-sulfonation after
nitroreduction to
hydroxylamine		 activation 390 14754874
SULT1C2 chemical PAH, metabolite (−)-1-hydroxyethylpyrene O-sulfonation activation 394 11535246
SULT1C2 chemical PAH, metabolite 1-hydroxymethylpyrene O-sulfonation activation 394 11535246
SULT1C2 chemical furan derivative 2,5-(bishydroxymethyl)furan O-sulfonation activation 411 21825114
SULT1C2 chemical furan derivative 5-methylfurfural O-sulfonation activation 411 21825114
SULT1C2 chemical furan derivative furfuryl alcohol O-sulfonation activation 411 21825114
SULT1C3 chemical PAH, metabolite (±)-, (+)-, and (−)-1-
hydroxyethylpyrene		 O-sulfonation activation 397 17936463
SULT1C3 chemical methylenedioxyphenyl
, benzodioxole,
metabolite		 1′-hydroxysafrole O-sulfonation, at high
conc.		 activation 397 17936463
SULT1C3 chemical PAH, metabolite 6-
hydroxymethylanthanthrene		 O-sulfonation potent
activation		 397 17936463
SULT1C3 chemical PAH, metabolite 6-
hydroxymethylbenzo[a]pyren
e		 O-sulfonation potent
activation		 397 17936463
SULT1E1 chemical PAH, metabolite (±)-, (+)-, and (−)-1-
hydroxyethylpyrene		 O-sulfonation potent
activation		 169, 394,
397 		10720750,
11535246,
17936463
SULT1E1 chemical PAH, metabolite 1-(1-pyrenyl)ethanol O-sulfonation activation 395 9141497
SULT1E1 chemical PAH, metabolite 10-hydroxy-7,8,9,10-
tetrahydrobenzo[a]pyrene		 O-sulfonation activation 395 9141497
SULT1E1 chemical PAH, metabolite 1-hydroxymethylpyrene O-sulfonation potent
activation		 394, 396,
397		 11535246,
10657971,
17936463
SULT1E1 chemical PAH, metabolite 4-
hydroxycyclopenta[def]chrys
ene		 O-sulfonation activation 169, 394 10720750,
11535246
SULT2A1 chemical PAH, metabolite (±)-, (+)-, and (−)-1-
hydroxyethylpyrene		 O-sulfonation activation 169, 394,
397 		10720750,
11535246,
17936463
SULT2A1 chemical PAH, metabolite 1-(1-pyrenyl)ethanol, I-HEP O-sulfonation activation 395 9141497
SULT2A1 chemical PAH, metabolite 1-hydroxy-3-
methylcholanthrene		 O-sulfonation activation 395 9141497
SULT2A1 chemical PAH, metabolite 1-hydroxymethylpyrene O-sulfonation potent
activation		 169, 394,
396 		10720750,
11535246,
10657971
SULT2A1 chemical PAH, metabolite 2-hydroxymethylpyrene O-sulfonation activation 395 9141497
SULT2A1 drug pregnane,
antiandrogen,
metabolite		 3α-hydroxycyproterone
acetate		 O-sulfonation activation 394 11535246
SULT2A1 chemical PAH, metabolite 6-
hydroxymethylbenzo[a]pyren
e		 O-sulfonation potent
activation		 169, 394 10720750,
11535246
SULT2A1 chemical PAH, metabolite 7-hydroxy-12-
methylbenz[a]anthracene		 O-sulfonation activation 394 9141497
SULT2A1 drug triphenylethyleneamin
e; antiestrogen,
estrogen receptor
modulator, metabolite		 α-hydroxytamoxifen O-sulfonation activation 412, 413 9855017,
15371299
SULT2A1 drug thioxanthenone;
schistosomicide		 hycanthone O-sulfonation potent
activation		 394, 395 11535246,
9141497
SULT2E1 chemical PAH 1-acetylpyrene O-sulfonation potent
activation		 399 11154739
SULT2E1 drug thioxanthenone;
schistosomicide		 hycanthone O-sulfonation activation 394 11535246
Open in a new tab

Table 4. Detoxication Reactions.

enzyme category subcategory compound reaction references PubMed ID
AKR1B1 natural
compound		 carbonyl, unsaturated 4-hydroxynonenal reduction 414 21329684
AKR1B1 natural
compound		 carbonyl, unsaturated acrolein reduction (low
activity)		 414 21329684
AKR1B1 natural
compound		 carbonyl, unsaturated crotonaldehyde reduction (low
activity)		 414 21329684
AKR1B1 natural
compound		 GSH conjugate,
metabolite		 GS-2-hexenal reduction (high
activity)		 414 21329684
AKR1B1 natural
compound		 carbonyl, unsaturated GS-4-hydroxynonanal reduction (high
activity)		 414 21329684
AKR1B1 natural
compound		 carbonyl, unsaturated GS-butanal reduction (high
activity)		 414 21329684
AKR1B1 natural
compound		 carbonyl, unsaturated GS-propanal reduction 414 21329684
AKR1B1 natural
compound		 GSH conjugate,
metabolite		 GS-trans-2-hexenal reduction 414 21329684
AKR1B1 natural
compound		 carbonyl, unsaturated trans-2,4-hexedinal reduction 414 21329684
AKR1B1 natural
compound		 carbonyl, unsaturated trans-2-hexenal reduction 414 21329684
AKR1B10 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 reduction 415 16381663
AKR1B10 natural
compound		 carbonyl, unsaturated 4-hydroxynonenal reduction (high
activity)		 414, 416,
417 		21329684
19013440,
19563777,
AKR1B10 natural
compound		 carbonyl, unsaturated 4-methylpentanal reduction 416 19013440
AKR1B10 natural
compound		 carbonyl 4-oxonon-2-enal reduction 416 19013440
AKR1B10 natural
compound		 carbonyl acrolein reduction 414, 417 21329684
19563777
AKR1B10 natural
compound		 carbonyl crotonaldehyde reduction (high
activity)		 414, 417 21329684
19563777
AKR1B10 natural
compound		 GSH conjugate,
metabolite		 GS-2-hexenal reduction 414 21329684
AKR1B10 natural
compound		 GSH conjugate,
metabolite		 GS-acrolein reduction 417 19563777
AKR1B10 natural
compound		 carbonyl, unsaturated GS-butanal reduction 414 21329684
AKR1B10 natural
compound		 GSH conjugate,
metabolite		 GS-crotonaldehyde reduction 417 19563777
AKR1B10 natural
compound		 carbonyl, unsaturated GS-propanal reduction (low
activity)		 414 21329684
AKR1B10 natural
compound		 GSH conjugate,
metabolite		 GS-trans-2, 4-hexadienal reduction 417 19563777
AKR1B10 natural
compound		 GSH conjugate,
metabolite		 GS-trans-2-hexenal reduction (high
activity)		 414, 417 21329684
19563777
AKR1B10 natural
compound		 carbonyl, unsaturated trans-2, 4-hexadienal reduction 417 19563777
AKR1B10 natural
compound		 carbonyl, unsaturated trans-2,4-hexedinal reduction 414 21329684
AKR1B10 natural
compound		 carbonyl, unsaturated trans-2-hexenal reduction (high
activity)		 414, 417 21329684
19563777
AKR1C1 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 reduction 418, 419 11037109,
11306090
AKR1C2 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 reduction 418, 419 11037109,
11306090
AKR1C4 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 reduction 418, 419 11037109,
11306090
AKR7A2 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 dialdehyde reduction 420, 421 10383892,
17537398
AKR7A3 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products,
metabolite		 aflatoxin B1 dialdehyde reduction 420-422 10383892,
17537398,
18416522
CYP1A1 chemical nitroarene 2-nitroanisole demethylation, O-
hydroxylation, C2-,
C2-C5-, and C2-
C6-		 423, 424 15144223,
17159769
CYP1A1 natural
compound		 nephrotoxin,
Aristolochia fangchi
compound, nitroarene		 aristolochic acid I hydroxylation, C8-
(major enzyme)		 99 22086975
CYP1A1 chemical PAH benzo[a]pyrene hydroxylation, 3-
(low Km, or
medium Km,
medium activity, or
high activity)		 44, 46, 48,
104-106,
425-427 		11238186,
7581497,
8293790,
9806168,
11513247,
8037457,
7766605,
9152602,
7703357
CYP1A1 chemical PAH benzo[a]pyrene hydroxylation 3-
(low activity)		 44, 138 11238186
9014198
CYP1A1 drug pyrido-carbazole;
antineoplastic, alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor, and DNA
binding		 ellipticine hydroxylation, C7-
and C9- (major
enzyme, low
activity)		 39, 187, 189 16936898,
15548707,
21683692
CYP1A1 chemical aza-aromatic Sudan I hydroxylation, C4′-
(high activity),
hydroxylation, C6-
(low activity);
oxidation, major
enzyme		 136, 137 12384524,
17159775
CYP1A2 chemical heterocyclic amine 2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (MeIQx)		 C8-oxidation
(carboxylic acid
form.)		 428, 429 10220313,
11258970
CYP1A2 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) hydroxylation
(AFM1 formation,
major enzyme and
reaction);
hydroxylation,
C3α- (AFQ1
formation, low
activity);
demethylation, O-
(AFP1 formation,
very low activity)		 176-178 7766804,
8261428,
12079611
CYP1A2 natural
compound		 nephrotoxin,
Aristolochia fangchi
compound, nitroarene		 aristolochic acid I hydroxylation, C8-
(major enzyme)		 99 22086975
CYP1A2 chemical PAH benzo[a]pyrene 3- hydroxylation
(low activity)		 46, 104,
106, 425-
427, 430 		7581497,
9806168,
8037457,
7766605,
9152602,
7703357,
1551116
CYP1A2 drug pyrido-carbazole;
antineoplastic, alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine hydroxylation, C7-
and C9- (major
enzyme in liver,
low activity)		 39, 187, 189 16936898,
15548707,
21683692
CYP1A2 drug pyrido-carbazole;
antineoplastic, alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine C7- hydroxylation
(major enzyme)		 187 15548707
CYP1B1 chemical PAH benzo[a]pyrene 3-hydroxylation 104, 222,
426 		9806168,
15958554,
9152602
CYP1B1 drug pyrido-carbazole;
antineoplastic, alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine hydroxylation, C7-
(very low activity)
and C9-		 187 15548707
CYP2A6 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 oxidation, N- 265 12975327
CYP2A6 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 oxidation, N- 265 12975327
CYP2A6 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) hydroxylation
(AFM1 formation,
low activity);
hydroxylation,
C3α- (AFQ1
formation, low
activity);
demethylation, O-
(AFP1 formation,
major reaction), at
high substrate
concentrations		 181 16385575
CYP2A13 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 oxidation, N- 265 12975327
CYP2A13 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) hydroxylation
(AFM1 formation,
low activity);
hydroxylation,
C3α- (AFQ1
formation, low
activity);
demethylation, O-
(AFP1 formation,
very low activity)		 181 16385575
CYP2B6 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 oxidation, N- 265 12975327
CYP2C19 chemical PAH benzo[a]pyrene hydroxylation 3- 138, 425,
427 		9014198,
7766605,
7703357,
CYP2C8 chemical PAH benzo[a]pyrene hydroxylation 3- 425, 427,
430 		7766605,
7703357,
1551116
CYP2C9 chemical PAH benzo[a]pyrene hydroxylation 3-
(major enzyme)		 138, 425,
427, 430 		9014198,
7766605,
7703357,
1551116
CYP2D6 drug pyrido-carbazole;
antineoplastic, alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine hydroxylation, C7-
(low activity) and
C9-		 187 15548707
CYP2E1 chemical nitroarene 2-nitroanisole demethylation, O-
hydroxylation, C2-,
C2-C5-, and C2-
C6- (major
enzyme)		 423, 424 15144223,
17159769
CYP2E1 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK)		 oxidation, N- 265 12975327
CYP2E1 chemical PAH benzo[a]pyrene hydroxylation 3-
(low activity)		 425, 427 7766605,
7703357
CYP3A4 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) hydroxylation,
C3α- (AFQ1
form.), medium
Km, medium
activity, major
reaction, major
enzyme		 176-178,
339 		7766804,
8261428,
12079611,
1643250
CYP3A4 chemical PAH benzo[a]pyrene hydroxylation 3-
(major enzyme)		 138, 425-
427, 430 		9014198,
7766605,
9152602,
7703357,
1551116
CYP3A4 drug pyrido-carbazole;
antineoplastic, alkaloid,
Apocyanaceae plants
compound,
topoisomerase II
inhibitor and DNA
binding		 ellipticine hydroxylation, C9-
(very low activity)		 187 15548707
CYP3A4 chemical aza-aromatic Sudan I hydroxylation, C4′-
and C6 (low
activity)		 136 12384524
CYP3A5 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) hydroxylation,
C3α- (AFQ1
form.)		 182, 365 16608170,
7893152
CYP3A7 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products		 aflatoxin B1 (AFB1) hydroxylation, C3α
- (AFQ1 formation)		 182 16608170
Epoxide
hydrolase,
EH 		chemical haloalkene, metabolite chloroprene epoxide (1-
chloroethenyl oxirane)		 hydrolysis 431 14565770
Epoxide
hydrolase,
EH 		natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products,
metabolite		 aflatoxin B1-8,9-epoxide hydrolysis,
aflatoxin-8,9-
dihydrodiol
formation		 432, 433 8781383,
9115980
Epoxide
hydrolase,
EH 		chemical PAH, metabolite benzo[a]pyrene-7,8-oxide hydrolysis to
benzo[a]pyrene-
7,8-diol		 52, 220 21028851,
10409402
GST physiological
compound		 estrogen, metabolite 4-hdroxyestrone-o-quinone covalent binding 434 18588320
GST chemical acrylic amide acrylamide GSH conjugation 435 19904761
GSTM chemical aromatic hydrocarbon,
alkyl benzene,
metabolite		 styrene 7,8-oxide GSH conjugation 436, 437 3224538,
3692493
GSTA1 chemical PAH dibenzo[a,l]pyrene GSH conjugation
after oxidation		 119 17509623
GSTA1 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 GSH conjugation
after oxidation		 119, 438 17509623,
9855012
GSTA1-1 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-dihydrodiol 9,10-epoxide		 GSH conjugation
(high activity)		 439-441 8706254,
11849043,
12067250
GSTA1-1 drug oxazaphosporine;
anticancer, mitrogen
mustard, alkylating,
metabolite		 4-hydroxycyclophosphamide GSH conjugation 442 7954469
GSTA1-1 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products,
metabolite		 aflatoxin B1-8,9-epoxide GSH conjugation 375, 443 8330352,
9675258
GSTA1-1 chemical PAH, metabolite benzo[c]chrysene-9,10-diol
11,12-epoxide		 GSH conjugation 439 8706254
GSTA1-1 chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol 1,2-epoxide		 GSH conjugation 439 8706254
GSTA1-1 chemical PAH, metabolite benzo[g]chrysene-11,12-diol
13,14-epoxide		 GSH conjugation 439 8706254
GSTA1-1 chemical PAH, metabolite chrysene-trans-1,2-
dihydrodiol-3,4-epoxide		 GSH conjugation 439 8706254
GSTA1-1 chemical PAH, metabolite dibenz[a,h]anthracene-3,4-
dihydrodiol 1,2-epoxide		 GSH conjugation 439 8706254
GSTA1-1 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol 13,14-epoxide		 GSH conjugation
(high activity)		 441 12067250
GSTA1-1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-acetoxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-acetoxy-PhIP)		 reduction in
reaction with GST
(major enzyme)		 406, 444 11535243,
8069858
GSTA1-1 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene
(N-OH-2-AAF)		 GSH conjugation 375 8330352
GSTA1-1 drug phosphoramide mustard
; anticancer, alkylating,
metabolite of
cyclophosphamide		 phosphoramide mustard GSH conjugation 442 7954469
GSTA1-2 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating,
metabolite		 4-hydroxycyclophosphamide GSH conjugation 442 7954469
GSTA1-2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-acetoxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-acetoxy-PhIP)		 reduction in
reaction with GST
(low activity)		 444 8069858
GSTA2-2 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products,
metabolite		 aflatoxin B1-8,9-epoxide GSH conjugation 420 10383892
GSTA2-2 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-acetoxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-acetoxy-PhIP)		 Reduction in
reaction with GST
(low activity)		 406 11535243
GSTA2-2 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol 13,14-epoxide		 GSH conjugation
(low activity)		 441 12067250
GSTA3-3 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol 13,14-epoxide		 GSH conjugation 441 12067250
GSTM1 chemical PAH, metabolite phenanthrene-9,10-epoxide GSH conjugation 445 16978029
GSTM1-1 natural
compound		 difuranocoumarin;
mycotoxin, produced
by Aspergillus species
on food products,
metabolite		 aflatoxin B1-8,9-epoxide GSH conjugation,
major enzyme		 432, 443,
433 		8781383,
9675258,
9115980
GSTM1-1 chemical hydroxylamine,
heterocyclic
amine,
metabolite		 N-acetoxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-acetoxy-PhIP)		 reduction in
reaction with GST
(low activity)		 404 11535243
GSTM1-1 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol 9,10-epoxide		 GSH conjugation 440, 446 11849043,
9403173
GSTM1-1 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 GSH conjugation
after oxidation		 51, 447 17525473,
12507920
GSTM1-1 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating,
metabolite		 4-hydroxycyclophosphamide GSH conjugation 442 7954469
GSTM1-1 chemical PAH benzo[a]pyrene GSH conjugation
after oxidation		 51 17525473
GSTM1-1 chemical PAH, metabolite benzo[c]chrysene-9,10-diol
11,12-epoxide		 GSH conjugation 446 9403173
GSTM1-1 chemical PAH, metabolite benzo[g]chrysene-11,12-diol
13,14-epoxide		 GSH conjugation 446 9403173
GSTM1-1 chemical PAH, metabolite chrysene-trans-1,2-diol-3,4-
epoxide		 GSH conjugation 446 9403173
GSTM1-1 chemical PAH dibenz[a,h]anthracene-3,4-
diol-1,2-epoxide		 GSH conjugation 446 9403173
GSTM1-1 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol 13,14-epoxide		 GSH conjugation 446 9403173
GSTP1-1 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol 9,10-epoxide		 GSH conjugation 438, 440,
446, 448,
449 		9855012,
11849043
9403173,
9299520,
9525277
GSTP1-1 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 GSH conjugation
after oxidation		 50, 450 16885195,
10344744
GSTP1-1 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating,
metabolite		 4-hydroxycyclophosphamide GSH conjugation 442 7954469
GSTP1-1 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating,
metabolite		 4-hydroxyifosfamide GSH conjugation 451 8555414
GSTP1-1 chemical quinoline 4-nitroquinoline 1-oxide
(NQO)		 GSH conjugation 452, 453 11108662,
15766272
GSTP1-1 chemical PAH 5-methylchrysene GSH conjugation
after oxidation		 83 18992797
GSTP1-1 chemical PAH, metabolite 5-methylchrysene-1,2-diol GSH conjugation
after oxidation		 83 18992797
GSTP1-1 chemical PAH, metabolite 5-methylchrysene-1,2-diol
3,4-epoxide		 GSH conjugation 454 9771942
GSTP1-1 chemical PAH, metabolite 6-methylchrysene-1,2-diol
3,4-epoxide		 GSH-conjugation 454 9771942
GSTP1-1 chemical PAH benzo[a]pyrene GSH conjugation
after oxidation		 50 16885195
GSTP1-1 chemical PAH, metabolite benzo[c]chrysene-9,10-diol
11,12-epoxide		 GSH conjugation 446, 455 9403173,
9827546
GSTP1-1 chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol-1,2-epoxide		 GSH conjugation 438, 446,
455, 456 		9855012,
9403173,
9827546,
9850062
GSTP1-1 chemical PAH, metabolite benzo[g]chrysene-11,12-diol-
13,14-epoxide		 GSH conjugation 438, 446,
455, 456 		9855012,
9403173,
9827546,
9850062
GSTP1-1 chemical PAH, metabolite chrysene-trans-1,2-
dihydrodiol-3,4-epoxide		 GSH conjugation 446, 448,
449 		9403173,
9299520,
9525277
GSTP1-1 chemical PAH, metabolite dibenz[a,h]anthracene-3,4-
diol-1,2-epoxide		 GSH-conjugation 446, 449 9403173,
9525277
GSTP1-1 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol-13,14-epoxide		 GSH conjugation 438, 446,
455, 457 		9855012,
9403173,
9827546,
9687571
GSTP1-1 drug oxazaphosporine;
anticancer, nitrogen
mustard, alkylating,
metabolite		 ifosfamide mustard GSH conjugation 451 8555414
GSTP1-1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-acetoxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-acetoxy-PhIP)		 reduction in
reaction with GST
(low activity)		 406, 444 11535243,
8069858
GSTP1-1 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene (N-OH-
2-AAF)		 GSH conjugation 375 8330352
GSTP1-1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 reduction in
reaction with GST		 458 11196146
GSTT1-1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-acetoxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-acetoxy-PhIP)		 reduction in
reaction with GST
(low activity)		 406 11535243
GSTT2-1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-acetoxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-acetoxy-PhIP)		 reduction in
reaction with GST
(low activity)		 406 11535243
NAD(P)H-
dependent
quinone
oxidoredu
ctase,
NQO1 		physiological
compound		 estrogen, metabolite 4-hydroxyestrone-o-quinone reduction (low
activity)		 434 18588320
NADH
cytochrom
e b5
reductase,
b5R;
cytochrom
e b5, CYB5 		chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 reduction 459 17040106
NADH
cytochrom
e b5
reductase,
b5R;
cytochrom
e b5, CYB5 		chemical arylamine, tobacco
smoke compound,
metabolite		 N-hydroxy-4-aminobiphenyl
(N-OH-4-ABP)		 reduction (low
activity)		 459, 460 17040106,
21447608
NAT1 chemical heterocyclic amine 2-amino-3-
methylimidazo[4,5-
f]quinolone (IQ)		 N-acetylation (low
activity)		 389 8353847
NAT1 chemical arylamine 2-aminofluorene (2-AF) N-acetylation (low
activity)		 389 8353847
NAT1 chemical PAH 2-naphthylamine N-acetylation (low
activity)		 389 8353847
NAT1 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl
(4-ABP)		 N-acetylation (low
activity)		 389 8353847
NAT1 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminobiphenyl
(N-acetoxy-4-ABP)		 N-acetylation (low
activity)		 389 8353847
NAT1 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene
(N-OH-2-AAF)		 N-acetylation (low
activity)		 389 8353847
NAT1 chemical arylamine, tobacco
smoke compound,
metabolite		 N-hydroxy-4-aminobiphenyl
(N-OH-4-ABP)		 N-acetylation (low
activity)		 389 8353847
NAT1 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-2-aminofluorene
(N-OH-2-AF)		 N-acetylation (low
activity)		 389 8353847
NAT2 chemical heterocyclic amine 2-amino-3-
methylimidazo[4,5-
f]quinolone (IQ)		 N-acetylation 389 8353847
NAT2 chemical arylamine 2-aminofluorene (2-AF) N-acetylation 389 8353847
NAT2 chemical arylamine 2-naphthylamine N-acetylation 389 8353847
NAT2 chemical arylamine, tobacco
smoke compound		 4-aminobiphenyl
(4-ABP)		 N-acetylation 389 8353847
NAT2 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminobiphenyl
(N-acetoxy-4-ABP)		 N-acetylation 389 8353847
NAT2 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene
(N-OH-2-AAF)		 N-acetylation 389 8353847
NAT2 chemical arylamine, tobacco
smoke compound,
metabolite		 N-hydroxy-4-aminobiphenyl
(N-OH-4-ABP)		 N-acetylation 389 8353847
NAT2 chemical hydroxylamine,
arylamine, metabolite		 N-hydroxy-2-aminofluorene
(N-OH-2-AF)		 N-acetylation 389 8353847
S-COMT physiological
compound		 estrogen, metabolite 2-hydroxyestradiol O-methylation, 2-
OH and 3-OH		 461, 462 11606384,
12360102
S-COMT physiological
compound		 estrogen, metabolite 2-hydroxyestrone O-methylation, 2-
OH and 3-OH		 462 12360102
S-COMT physiological
compound		 estrogen, metabolite 4-hydroxyestradiol O-methylation, 4-
OH		 462 12360102
S-COMT physiological
compound		 estrogen, metabolite 4-hydroxyestrone O-methylation, 4-
OH		 462 12360102
S-COMT chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 O-methylation 463 21622560
S-COMT chemical PAH, metabolite 12-methylbenz[a]anthracene-
3,4-diol		 O-methylation 463 21622560
S-COMT chemical PAH, metabolite 5-methylchrysene-1,2-diol O-methylation 463 21622560
S-COMT chemical PAH, metabolite 5-methylchrysene-7,8-diol O-methylation 463 21622560
S-COMT chemical PAH, metabolite 7,12-
dimethylbenz[a]anthracene-
3,4-diol		 O-methylation 463 21622560
S-COMT chemical PAH, metabolite 7-methylbenz[a]anthracene-
3,4-diol		 O-methylation 463 21622560
S-COMT chemical PAH, metabolite benz[a]anthracene-3,4-diol O-methylation (low
activity)		 463 21622560
S-COMT chemical PAH, metabolite benzo[c]phenanthrene-3,4-
diol		 O-methylation 463 21622560
S-COMT chemical PAH, metabolite benzo[g]chrysene-11,12-diol O-methylation 463 21622560
S-COMT chemical PAH, metabolite chrysene-1,2-diol O-methylation 463 21622560
S-COMT chemical PAH, metabolite chrysene-3,4-diol O-methylation (low
activity)		 463 21622560
SULT chemical heterocyclic amine 2-amino-3-
methylimidazo[4,5-
f]quinolone (IQ)		 N-sulfamate
formation (low
activity)		 464 7744696
SULT chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (N-OH-MeIQx)		 N-sulfation after N-
hydroxylation		 429, 465 11258970
8844796
UGT chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-3,8-
dimethylimidazo[4,5-
f]quinoxaline (N-OH-MeIQx)		 N-glucuronidation 429, 465 11258970
8844796
UGT1A1 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 O-glucuronidation 466 11929814
UGT1A1 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 N2- (major
metabolite) and
N3-glucuronidation		 467, 468 11408353,
17638922
UGT1A1 physiological
compound		 estrogen, metabolite 2-hydroxyestradiol O-glucuronidation 469 15117964
UGT1A1 physiological
compound		 estrogen, metabolite 2-hydroxyestrone O-glucuronidation 469 15117964
UGT1A1 physiological
compound		 estrogen, metabolite 4-hydroxyestrone O-glucuronidation 469 15117964
UGT1A1 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 O-glucuronidation 470 21780761
UGT1A1 physiological
compound		 estrogen 17β-estradiol O-glucuronidation 469 15117964
UGT1A1 physiological
compound		 estrogen estrone O-glucuronidation 469 15117964
UGT1A1 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 N2- (major
metabolite) and
N3-
glucuronidation,
major enzyme		 146, 467,
468, 471,
472 		11375903,
11408353,
17638922,
15310245,
15708579
UGT1A1 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation
(low activity)		 402, 473,
474 		12034366,
16480962,
17664247
UGT1A3 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 N2- and N3-
glucuronidation		 475 10357796
UGT1A3 physiological
compound		 estrogen, metabolite 2-hydroxyestradiol O-glucuronidation
(low activity)		 469 15117964
UGT1A3 physiological
compound		 estrogen, metabolite 2-hydroxy-estrone O-glucuronidation
(low activity)		 469 15117964
UGT1A3 physiological
compound		 estrogen, metabolite 4-hydroxyestrone O-glucuronidation 469 15117964
UGT1A3 physiological
compound		 estrogen 17β-estradiol O-glucuronidation 469 15117964
UGT1A3 physiological
compound		 estrogen estrone O-glucuronidation 469 15117964
UGT1A3 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene (N-OH-
2-AAF)		 N-glucuronidation
(low activity)		 146 11375903
UGT1A3 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 N2- and N3-
glucuronidation
(major metabolite)		 146, 467,
468, 471 		11375903,
11408353,
17638922,
15310245
UGT1A4 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 N2- and N3-
glucuronidation
(major metabolite),
low activity		 467, 468 11408353,
17638922
UGT1A4 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 N-glucuronidation 476-478 14871856,
14709623,
18238858
UGT1A4 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen N-glucuronidation 278, 402,
473, 474,
479 		16884532,
12034366,
16480962,
17664247,
15135306
UGT1A4 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 O-glucuronidation 470 21780761
UGT1A4 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 N2- (major
metabolite) and
N3-glucuronidation		 467, 468,
471 		11408353,
17638922,
15310245
UGT1A4 chemical tobacco-specific
nitrosamine		 N’-nitrosoanabasine O-glucuronidation 478 18238858
UGT1A4 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator		 tamoxifen N-glucuronidation 278 16884532
UGT1A6 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation
(low activity)		 473 16480962
UGT1A6 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene
(N-OH-2AAF)		 N-glucuronidation
(low activity)		 146 11375903
UGT1A6 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 N-glucuronidation
(low activity)		 146 11375903
UGT1A7 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 O-glucuronidation 466 11929814
UGT1A7 physiological
compound		 estrogen, metabolite 2-hydroxyestradiol O-glucuronidation 469 15117964
UGT1A7 physiological
compound		 estrogen, metabolite 2-hydroxyestrone O-glucuronidation 469 15117964
UGT1A7 physiological
compound		 estrogen, metabolite 4-hydroxyestrone O-glucuronidation 469 15117964
UGT1A7 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation
(low activity)		 473, 474 16480962,
17664247
UGT1A7 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 O-glucuronidation 470 21780761
UGT1A7 physiological
compound		 estrogen 17β-estradiol O-glucuronidation
(low activity)		 469 15117964
UGT1A7 physiological
compound		 estrogen estrone O-glucuronidation
(low activity)		 469 15117964
UGT1A7 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene (N-OH-
2-AAF)		 N-glucuronidation
(high activity)		 146 11375903
UGT1A7 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 N2- and N3-
glucuronidation
(low activity)		 146, 467,
468, 471 		11375903,
11408353,
17638922,
15310245
UGT1A8 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 N2- and N3-
glucuronidation		 466 10357796
UGT1A8 physiological
compound		 estrogen, metabolite 2-hydroxyestradiol O-glucuronidation 469 15117964
UGT1A8 physiological
compound		 estrogen, metabolite 2-hydroxyestrone O-glucuronidation 469 15117964
UGT1A8 physiological
compound		 estrogen, metabolite 4-hydroxyestrone O-glucuronidation 469 15117964
UGT1A8 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation
(low activity)		 473, 474 16480962,
17664247
UGT1A8 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 O-glucuronidation 470 21780761
UGT1A8 physiological
compound		 estrogen 17β-estradiol O-glucuronidation 469 15117964
UGT1A8 physiological
compound		 estrogen estrone O-glucuronidation
(low activity)		 469 15117964
UGT1A8 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene (N-OH-
2-AAF)		 N-glucuronidation
(low activity)		 146 11375903
UGT1A8 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 N2- (major
metabolite) and
N3-glucuronidation		 146, 467,
468, 471 		11375903,
11408353,
17638922,
15310245
UGT1A9 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 O-glucuronidation 466 11929814
UGT1A9 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 N2- (major
metabolite) and
N3-
glucuronidation,
low activity		 467, 468,
475 		11408353,
17638922,
10357796
UGT1A9 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 O-glucuronidation 477, 480 14709623,
11038164
UGT1A9 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation
(low activity)		 402, 473,
474 		12034366,
16480962,
17664247
UGT1A9 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 O-glucuronidation
(high activity)		 470 21780761
UGT1A9 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene (N-OH-
2-AAF)		 N-glucuronidation
(high activity)		 146 11375903
UGT1A9 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 N2- and N3-
glucuronidation
(major metabolite)		 146, 467,
468, 471,
475 		11375903,
11408353,
17638922,
15310245,
10357796
UGT1A10 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 O-glucuronidation
(major enzyme)		 466, 481 11929814,
16510539
UGT1A10 chemical heterocyclic amine 2-amino-1-methyl-6-
phenylimidazo[4,5-
b]pyridine (PhIP)		 N2- and N3-
glucuronidation		 468, 475 17638922,
10357796
UGT1A10 physiological
compound		 estrogen, metabolite 2-hydroxyestradiol O-glucuronidation
(high activity)		 469 15117964
UGT1A10 physiological
compound		 estrogen, metabolite 2-hydroxyestrone O-glucuronidation 469 15117964
UGT1A10 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 O-glucuronidation 482 20007297
UGT1A10 physiological
compound		 estrogen, metabolite 4-hydroxyestrone O-glucuronidation
(high activity)		 469 15117964
UGT1A10 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation
(low activity)		 473, 474 16480962,
17664247
UGT1A10 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 O-glucuronidation 468 21780761
UGT1A10 physiological
compound		 estrogen 17β-estradiol O-glucuronidation
(high activity)		 467 15117964
UGT1A10 physiological
compound		 estrogen estrone O-glucuronidation
(high activity)		 467 15117964
UGT1A10 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene (N-OH-
2-AAF)		 N-glucuronidation
(low activity)		 146 11375903
UGT1A10 chemical hydroxylamine,
heterocyclic amine,
metabolite		 N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-
b]pyridine (N-OH-PhIP)		 N2- (major
metabolite) and
N3-
glucuronidation,
high activity		 146, 465,
466, 469 		11375903,
11408353,
17638922,
15310245
UGT2A1 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 O-glucuronidation 483 21164388
UGT2A1 chemical PAH, metabolite 5-methylchrysene-1,2-diol O-glucuronidation 481 21164388
UGT2B10 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 O-glucuronidation 478 18238858
UGT2B10 chemical tobacco-specific
nitrosamine		 N’-nitrosoanabasine O-glucuronidation 478 18238858
UGT2B10 chemical tobacco-specific
nitrosamine		 N’-nitrosoanatabine O-glucuronidation 478 18238858
UGT2B10 chemical tobacco-specific
nitrosamine		 N’-nitrosoanatabine O-glucuronidation 468, 478 17638922,
18238858
UGT2B10 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 O-glucuronidation 478 18238858
UGT2B10 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 O-glucuronidation 468, 478 17638922,
18238858
UGT2B15 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation 402, 473,
474 		12034366,
16480962,
17664247
UGT2B17 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 O-glucuronidation 484 17416778
UGT2B17 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation 474 17664247
UGT2B7 chemical PAH, metabolite (+)- and (−)-benzo[a]pyrene-
7,8-diol		 O-glucuronidation 466 11929814
UGT2B7 chemical tobacco-specific
nitrosamine		 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL)		 O-glucuronidation 476, 477,
480 		14871856,
14709623,
11038164
UGT2B7 chemical PAH, metabolite dibenzo[a,l]pyrene-11,12-
diol		 O-glucuronidation 470 21780761
UGT2B7 chemical hydroxamic acid,
heterocyclic amine,
metabolite		 N-hydroxy-2-
acetylaminofluorene (N-OH-
2-AAF)		 N-glucuronidation 146 11375903
UGT2B7 drug triphenylethyleneamine
; antiestrogen, estrogen
receptor modulator,
metabolite		 4-hydroxytamoxifen O-glucuronidation 474 17664247
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Table 2. Bioactivation of Natural Compounds.

enzyme category subcategory compound reaction remarks references PubMed ID
CYP1A1 natural
compound		 indole, alkylating,
pulmonary toxin; higher
concentrations in
mammalian digestive
tract and coal tar		 3-methylindole (skatole)
epoxidation (3-
methyloxindole
formation);
dehydrogenation
(desaturation, 3-
methyleneindolenine
form), low Km, medium		 activity, high efficiency activation 75-78 8558432,
11408359,
12563100,
20795680
CYP1A1 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) epoxidation 8,9-;
oxidation		 activation 41, 57, 61,
93, 94 		8674051,
15279838,
11377247,
7923587,
8200084
CYP1A1 natural
compound		 phenanthroic acid
derivative; nephrotoxin,
found in the
Aristolochiaceae family
of plants		 aristolochic acid I nitroreduction potent
activation		 96-99 11511187,
15386410,
16125300,
22086975
CYP1A1 natural
compound		 phenanthroic acid
derivative; nephrotoxin,
found in the
Aristolochiaceae family
of plants		 aristolochic acid II nitroreduction activation 96-99 11511187,
15386410,
16125300,
22086975
CYP1A1 physiological
compound		 estrogen 17β−estradiol C2-hydroxylation (major
reaction, medium Km,
high activity, high
efficiency), major
metabolite and major
extrahepatic enzyme;
C4-hydroxylation (minor
reaction, medium Km,
medium efficiency, low
activity), oxidation, 3,4-
quinone formation
(lower activity);
oxidation, 2,3-quinone
formation; C16α-
hydroxylation (high Km,
low activity)		 potent
activation		 71, 106,
121-130 		9721189,
8037457,
7826886,
9625734,
9054608,
9667077,
8930523,
11555828,
12865317,
15784278,
16112414,
17570247
CYP1A1 physiological
compound		 estrogen estrone C2-hydroxylation (major
reaction, medium Km,
low activity), oxidation,
2,3-quinone formation;
C4-hydroxylation
(medium Km, low
activity, or medium
activity); C16α-
hydroxylation (minor
reaction, very low
activity)		 activation 49, 127,
130, 131 		10426814,
12865317,
17570247,
15805301
CYP1A1 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 oxidation activation 132, 133 11774366,
12214673
CYP1A2 natural
compound		 furanoterpene produced
by sweet potatoes
infected with Fusarium
solani; pulmonary toxin,
alkylating		 4-ipomeanol oxidation (major
enzyme)		 activation 172, 173 1651809,
15892579
CYP1A2 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) epoxidation (both exo-
8,9- and endo-8,9-);
oxidation		 activation 11, 12, 13,
41, 42, 57,
61, 93, 94,
162, 175-
182 		2492107
2655891,
2509067,
8674051,
7955101,
15279838,
11377247,
7923587,
8200084,
10023085,
2162057
7766804,
8261428,
12079611,
1902334,
11782366,
16385575,
16608170
CYP1A2 natural
compound		 phenanthroic acid
derivative; nephrotoxin,
found in the
Aristolochiaceae family
of plants		 aristolochic acid I nitroreduction potent
activation		 96-99 11511187,
15386410,
16125300,
22086975
CYP1A2 natural
compound		 phenanthroic acid
derivative; nephrotoxin,
found in the
Aristolochiaceae family
of plants		 aristolochic acid II nitroreduction potent
activation		 96-99 11511187,
15386410,
16125300,
22086975
CYP1A2 natural
compound		 bicyclic monoterpene Δ3-carene epoxidation (high Km,
medium activity)		 activation 183 16379671
CYP1A2 physiological
compound		 estrogen 17β-estradiol C2-hydroxylation (major
reaction, medium Km,
medium activity,
medium efficiency),
major metabolite and
major enzyme in liver;
C4-hydroxylation (minor
reaction); C16α-
hydroxylation (major
enzyme, high Km, no
activity, or low activity)		 activation 71, 106,
122-124,
126-129,
190-194 		9721189,
8037457,
9625734,
9054608,
9667077,
11555828,
12865317,
15784278,
16112414,
1449532,
9635876,
11454902,
11741520,
14703066
CYP1A2 natural
compound		 alkenylbenzene; occurs
in a variety of foods
including essential oils of
tarragon, sweet basil,
sweet fennel, anis		 estragole C1′-hydroxylation
(major enzyme, medium
Km, low activity)		 potent
activation		 195-197 17407329,
15914212,
21459083
CYP1A2 physiological
compound		 estrogen estrone C2-hydroxylation
(medium Km, high
activity, major
metabolite); C4-
hydroxylation (medium
Km, medium activity,
very low activity);
C16α-hydroxylation
(minor reaction, very
low activity)		 activation 49, 122,
123, 127,
128, 191,
192, 198 		10426814,
9625734,
9054608,
12865317,
15784278,
9635876,
11454902,
16537715
CYP1A2 natural
compound		 phenylpropene, from
Rhizoma acorigraminei 		methyleugenol C1′-hydroxylation
(medium Km, major
enzyme)		 activation 196, 199 15914212,
16411663
CYP1A2 natural
compound		 furanoxanthone;
mycotoxin, produced by
Aspergillus species		 sterigmatocystin oxidation activation 41 8674051
CYP1B1 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) oxidation activation 61, 210,
217 		11377247,
16551781,
9106248
CYP1B1 physiological
compound		 estrogen 17β-estradiol C4-hydroxylation (major
enzyme, medium Km,
medium activity,
medium and low
efficiency), oxidation,
3,4-quinone formation;
C2-hydroxylation (low
activity, minor reaction),
oxidation, 2,3-quinone
formation; C16α-
hydroxylation (minor
enzyme, medium and
high Km, low activity)		 potent
activation		 49, 71,
121-130,
194, 211,
221, 225-
228 		10426814,
9721189,
7826886,
9625734,
9054608,
9667077,
8930523,
11555828,
12865317,
15784278,
16112414,
17570247,
14703066,
11719446,
11465393,
8790407,
7568105,
10862525,
10910054
CYP1B1 physiological
compound		 estrogen estrone C4-hydroxylation (low
Km, major reaction); C2-
hydroxylation (low
activity, minor reaction),
oxidation, 2,3-quinone
formation;		 potent
activation		 49, 127,
128, 130,
198 		10426814,
12865317,
15784278,
17570247,
16537715
CYP2A6 natural
compound		 alkenylbenzene; occurs
in a variety of foods		 including essential oils of
tarragon, sweet basil,
sweet fennel, anis
estragole		 C1′-hydroxylation
(major enzyme, medium
Km, medium activity)		 potent
activation		 195, 197 17407329,
21459083
CYP2A6 natural
compound		 furanocoumarin; anti-
psoriatic, photosensitizer,
found in several species
of plants		 methoxalen (8-
methoxypsoralen,
xanthotoxin)		 epoxidation
(furanoepoxide
formation) and
hydrolysis		 activation 140 17584015
CYP2A6 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 hydroxylation C5′-
(lactol formation,
medium Km, high to
medium activity);
oxidation (major
enzyme)		 activation 132-134,
244, 256-
258 		11774366,
12214673,
11600130,
15651850,
10837014,
9276639,
7646564
CYP2A6 natural
compound		 methylenedioxypheny,
benzodioxole		 safrole C1′-hydroxylation
(major enzyme at low
concentrations), medium
Km, medium activity		 activation 195, 196,
259, 260 		17407329,
15914212,
15377158,
15310247
CYP2A13 natural
compound		 indole, alkylating,
pulmonary toxin; in
higher concentrations in
mammalian digestive
tract and coal tar		 3-methylindole, skatole dehydrogenation
(desaturation, 3-
methyleneindolenine
formation, low Km,
medium activity, high
efficiency); epoxidation
(3-methyloxindole
formation)		 potent
activation		 77, 261 20795680,
19608696
CYP2A13 chemical difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) epoxidation 8,9-;
oxidation		 potent
activation		 181, 265 16385575,
16917071
CYP2A13 natural
compound		 furanocoumarin; anti-
psoriatic, photosensitiser,
found in bergamot
essential oil, in other
citrus essential oils, and
in grapefruit juice		 bergapten (5-
methoxypsoralen)		 epoxidation and
hydrolysis to dihydrodiol		 activation 267 20798279
CYP2A13 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 hydroxylation C5′-
(lactol formation,
medium Km, high
activity) and C2′- (keto
alcohol formation,
medium Km, low
activity)		 activation 258, 266 19074523,
15651850
CYP2C9 natural
compound		 phenylpropene; from
Rhizoma acorigraminei 		methyleugenol C1′-hydroxylation
(medium activity, high
Km), at high
concentration		 activation 196, 199 15914212,
16411663
CYP2C19 natural
compound		 furanoterpene produced
in sweet potatoes
infected with Fusarium
solani; pulmonary toxin,
alkylating		 4-ipomeanol oxidation (major
enzyme)		 activation 173 15892579
CYP2D6 natural
compound		 furanoterpene produced
in sweet potatoes
infected with Fusarium
solani; pulmonary toxin,
alkylating		 4-ipomeanol oxidation activation 173 15892579
CYP2D6 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) oxidation activation 61 11377247
CYP2E1 natural
compound		 furanoterpene produced
in sweet potatoes
infected with Fusariumsolani; pulmonary toxin,
alkylating		 4-ipomeanol oxidation activation 173 15892579
CYP2E1 natural
compound		 carbamic acid derivative;
fermentation by-product		 ethyl carbamate (urethane) oxidation to vinyl
carbamate epoxide		 activation 107, 282,
310-312 		1486866,
1664256,
9344892,
9150748,
11181492
CYP2E1 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 hydroxylation C5′-
(lactol formation, low
activity)		 activation 134, 244,
247,
256, 265 		11600130,
10837014,
1423839,
9276639,
7646564
CYP2F1 natural
compound		 indole, alkylating,
pulmonary toxin; present
in higher concentrations		 in mammalian digestive
tract and coal tar		 3-methylindole, skatole dehydrogenation
(desaturation, 3-
methyleneindolenine
form., low Km, medium
activity, high efficiency),
major enzyme		 potent
activation		 75-79, 334,
335 		8558432,
11408359,
12563100,
20795680,
10383923,
17962375
CYP2F1 natural
compound		 furanoterpene produced
in sweet potatoes
infected with Fusarium
solani; pulmonary toxin,
alkylating		 4-ipomeanol oxidation activation 172 1651809
CYP2W1 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) oxidation activation 210 16551781
CYP2W1 natural
compound		 furanoxanthone;
mycotoxin, produced by
Aspergillus species		 sterigmatocystin oxidation activation 210 16551781
CYP3A4 natural
compound		 furanoterpene produced
in sweet potatoes
infected with Fusarium
solani; pulmonary toxin,
alkylating		 4-ipomeanol epoxidation; oxidation,
minor enzyme		 activation 140, 172,
173 		17584015,
1651809,
15892579
CYP3A4 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) epoxidation exo-C8,9-
(major activating
enzyme), oxidation		 activation 11, 12, 41,
57, 61,
175-180,
182, 336,
339-341 		2492107,
2655891,
7955101,
15279838,
11377247,
2162057,
7766804,
8261428,
12079611,
1902334,
11782366,
16608170,
9328287,
1643250,
7545582,
7850790
CYP3A4 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin G1 (AFG1) oxidation activation 11, 12, 107,
341-343 		2492107,
2655891,
1486866,
8082563,
7850790,
352361,
12849689
CYP3A4 physiological
compound		 estrogen 17β-estradiol C2-hydroxylation (major
reaction, major enzyme,
medium Km, medium
efficiency, high activity),
major metabolite and
major enzyme in liver;
oxidation, 2,3-quinone
formation (lower
activity); C4-
hydroxylation (minor
reaction, major enzyme,
medium Km, medium
activity, medium
efficiency); oxidation,
3,4-quinone formation;
C16α-hydroxylation
(high Km, low activity)		 activation 107, 122-
124, 126-
130, 190-
193, 346,
347 		1486866,
9625734,
9054608,
9667077,
11555828,
12865317,
15784278,
16112414,
17570247,
1449532,
9635876,
11454902,
11741520,
10821664,
12124305
CYP3A4 physiological
compound		 estrogen estrone C2-hydroxylation (high
Km, major metabolite,
low activity); oxidation,
2,3-quinone formation;
C4-hydroxylation (high
Km, low activity, major
enzyme); C16α-
hydroxylation (high Km,
low activity, major
enzyme)		 activation 49, 122-
124, 127,
128, 130,
191, 192 		10426814,
9625734,
9054608,
9667077,
12865317,
15784278,
17570247,
9635876,
11454902
CYP3A4 natural
compound		 alkaloid, pyrrolizidine,
genotoxic		 monocrotaline dehydrogenation activation 356 15649625
CYP3A4 natural
compound		 nitrosamine, tobacco-
specific		 N’-nitrosonornicotine (N-
nitrosonornicotine, NNN)		 hydroxylation C2′- (keto
alcohol formation);
oxidation		 activation 132, 133,
256, 257 		11774366,
12214673,
9276639,
7646564
CYP3A4 natural
compound		 pyrrolizidine alkaloid
from Senecio retrorsus 		retrorsine dehydrogenation activation 356 15649625
CYP3A4 natural
compound		 pyrrolizidine alkaloid,
food contaminant (meat,
milk, and honey)		 riddelliine dehydrogenation activation 356 15649625
CYP3A4 natural
compound		 pyrrolizidine alkaloid,
genotoxic		 senecionine dehydrogenation activation 107, 357 1486866,
2009596
CYP3A4 natural
compound		 furanoxanthone;
mycotoxin, produced by
Aspergillus species		 sterigmatocystin oxidation activation 11, 12, 66,
107, 336,
341 		2492107,
2655891,
9685642,
1486866,
9328287,
7850790
CYP3A5 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) epoxidation exo-8,9-
(major reaction);
oxidation		 activation 182, 365 16608170,
7893152
CYP3A5 physiological
compound		 estrogen 17β-estradiol C2-hydroxylation; C4-
hydroxylation (major
reaction); C16α-
hydroxylation (low
activity)		 activation 127, 128,
191, 192,
347 		12865317,
15784278,
9635876,
11454902,
12124305
CYP3A5 chemical tobacco-specific
nitrosamine		 N’-nitrosoanabasine oxidation activation 132, 133 11774366,
12214673
CYP3A7 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin B1 (AFB1) epoxidation exo-C8,9-;
oxidation		 activation 107, 182,
336, 338,
341, 366 		1486866,
16608170,
9328287,
9493761,
7850790,
9044840
CYP3A7 natural
compound		 difuranocoumarin;
mycotoxin, produced by
Aspergillus species on
food products		 aflatoxin G1 (AFG1) oxidation activation 341 7850790
CYP3A7 physiological
compound		 estrogen 17β-estradiol C2-hydroxylation
(medium Km, low
activity, major reaction);
C4-hydroxylation (low
activity, high Km);
C16α-hydroxylation
(very low activity, high
Km)		 activation 127, 128,
347 		12865317,
15784278,
12124305,
CYP3A7 physiological
compound		 estrogen estrone C2-hydroxylation
(medium Km, medium
activity); C4-
hydroxylation (low
activity, medium Km);
C16α-hydroxylation
(medium Km, medium
activity)		 activation 127, 128 12865317,
15784278
CYP3A7 natural
compound		 furanoxanthone;
mycotoxin, produced by
Aspergillus species		 sterigmatocystin oxidation activation 336, 338,
341 		9328287,
9493761,
7850790
CYP4B1 natural
compound		 furanoterpene produced
in sweet potatoes
infected with Fusarium
solani; pulmonary toxin,
alkylating		 4-ipomeanol oxidation activation 172 1651809
CYP19A1
(aromatase) 		physiological
compound		 estrogen estradiol 17β- C2-hydroxylation
(medium Km)		 activation 125, 369 8930523,
8476762
CYP19A1
(aromatase) 		physiological
compound		 estrogen estrone C2-hydroxylation
(medium Km)		 activation 125, 369 8930523,
8476762
SULT1A1 natural
compound		 1-methoxy-3-
indolylmethyl
glucosinolate breakdown
product, in many
Brassica vegetables		 1-methoxy-3-
indolylmethyl-alcohol		 O-sulfonation activation 398 20846518
SULT1A1 natural
compound		 nephrotoxin, Aristolochia
fangchi compound,
nitroarene		 aristolochic acids I and II O-sulfonation after
nitroreduction to
hydroxylamine		 potent
activation		 404 16161050
SULT1A3 natural
compound		 alkenylbenzene; occurs
in a variety of foods
including essential oils of
tarragon, sweet basil,
sweet fennel, anis,
metabolite		 1′-hydroxyestragole O-sulfonation activation 197, 401 21459083,
22072630
SULT1A3 natural
compound		 alkenylbenzene; occurs
in a variety of foods
including essential oils of
tarragon, sweet basil,
sweet fennel, anis		 estragole O-sulfonation after C1′-
hydroxylation		 activation 401 22072630
SULT1B1 natural
compound		 nephrotoxin, Aristolochia
fangchi compound,
nitroarene		 aristolochic acids I and II O-sulfonation after
nitroreduction to
hydroxylamine		 activation 394 16161050
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Table 3. Activation of Drugs.

enzyme category subcategory compound reaction remarks references PubMed ID
COX-1 drug pyrido-carbazole; antineoplastic,
alkaloid, Apocyanaceae plant
compound, topoisomerase II inhibitor,
and DNA binding		 ellipticine oxidation activation 39, 40 16936898,
21753906
CYP1A1 drug imidazole; anticancer, alkylating dacarbazine N-demethylation (major
extrahepatic enzyme)		 activation 111 10473105
CYP1A1 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide oxidation (at high conc.) activation 87 20507880
CYP1A2 drug imidazole; anticancer, alkylating dacarbazine N-demethylation (major
enzyme)		 potent
activation		 111 10473105
CYP1A2 drug pyrido-carbazole; antineoplastic,
alkaloid, apocyanaceae plant
compound, topoisomerase II inhibitor
and DNA binding		 ellipticine hydroxylation, C12- and
C13- (low activity)		 activation 39, 40, 185-
189 		16936898,
21753906,
11755121,
12123750,
15548707,
17197724,
21683692
CYP1A2 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide oxidation (at high
concentration)		 activation 87 20507880
CYP1B1 drug pyrido-carbazole; antineoplastic,
alkaloid, Apocyanaceae plant
compound, topoisomerase II inhibitor
and DNA binding		 ellipticine oxidation activation 39, 185-188 16936898,
11755121,
12123750,
15548707,
17197724
CYP2A6 drug oxazaphosporine; anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (minor
enzyme, high Km); oxidation		 activation 101, 108,
251-254 		11377097,
19501186,
8242617,
9010702,
10348794,
10692561
CYP2A6 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation (minor
reaction, high Km); oxidation
(at high concentration)		 activation 87, 251, 253 20507880,
8242617,
10348794
CYP2B6 drug oxazaphosporine; anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (major
enzyme, major reaction, high
Km, high activity); oxidation		 potent
activation		 74, 101, 108,
251-254, 271,
275 		11360624,
11377097,
19501186,
8242617,
9010702,
10348794,
10692561,
9280407,
15919850
CYP2B6 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation
stereoselective for (S)-(high
Km, major enzyme);
oxidation (at high
concentrations)		 activation 87, 251-254,
275-277, 355 		20507880,
8242617,
10348794,
10692561,
15919850,
10534317,
15821045,
16854777
CYP2C8 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation (minor
enzyme, high Km), oxidation
(at high concentrations)		 activation 87, 251, 253 20507880,
8242617,
10348794
CYP2C9 drug oxazaphosporine; anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (low Km,
low activity, major enzyme at
low concentration); oxidation		 activation 101, 108,
251-254 		11377097,
19501186,
8242617,
9010702,
10348794,
10692561
CYP2C9 Drug Oxazaphosporine; Anticancer,
Nitrogen mustard alkylating		 Ifosfamide C4-hydroxylation (low Km),
Oxidation (at high
concentrations)		 activation 87, 251 8242617,
20507880
CYP2C9 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation (low Km),
oxidation (at high
concentration)		 activation 86, 251 20507880,
8242617
CYP2C19 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation
stereoselective for (S)-
(minor reaction, high Km),
oxidation (at high
concentration)		 activation 87, 251, 253,
276 		20507880,
8242617,
10348794,
10534317
CYP2D6 drug pyrido-carbazole; antineoplastic,
alkaloid, Apocyanaceae plant
compound, topoisomerase II inhibitor
and DNA binding		 ellipticine oxidation N2-; hydroxylation,
C13-(low activity)		 activation 39, 40, 187,
188 		16936898,
21753906,
15548707,
17197724
CYP2D6 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide oxidation (at high
concentration)		 activation 87 20507880
CYP2E1 drug platinum-containing; anticancer cisplatin oxidation activation 303, 304 16251482,
17761302
CYP2E1 drug imidazole; anticancer, alkylating dacarbazine N-demethylation activation 111 10473105
CYP3A4 drug oxazaphosporine; anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation; oxidation activation 108, 251-254,
275, 344 		19501186,
8242617,
9010702,
10348794,
10692561,
9923542,
15919850
CYP3A4 drug pyrido-carbazole; antineoplastic,
alkaloid, Apocyanaceae plants
compound, topoisomerase II inhibitor
and DNA binding		 ellipticine hydroxylation, C13- (major
enzyme) and C12- (minor
reaction); oxidation N2-
(major enzyme)		 potent
activation		 39, 40, 287-
290, 345 		16936898,
21753906,
11755121,
12123750,
15548707,
17197724,
20576524
CYP3A4 drug estradiol derivative; estrogen,
contraceptive		 17α-ethynylestradiol
(ethinylestradiol
17α-)		 oxygenation (2-
hydroxylation, 17α-
inactivation)		 activation 140, 348 17584015,
17251390
CYP3A4 drug antimitotic, epipodophyllotoxin,
topoisomerase II inhibitor		 etoposide (VP-16) O-demethylation (catechol
formation), high Km, high
activity, major enzyme		 activation 349-351 8114683,
9456308,
17168690
CYP3A4 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation
stereoselective for (R)- (high
Km, high activity); oxidation
at high concentration		 potent
activation		 87, 251, 275-
277, 344,
352-355 		20507880,
8242617,
10692561,
15919850,
10534317,
15821045,
9923542,
8161344,
10101149,
10348794,
16854777
CYP3A4 drug triphenylethyleneamine; antiestrogen,
estrogen receptor modulator		 tamoxifen Cα-hydroxylation (major
enzyme); catechol formation;
oxidation, at high
concentration		 activation 87, 354, 358-
364 		20507880,
10348797,
12018981,
12971802,
14678348,
15159443,
16533026,
12124303,
12419838
CYP3A5 drug oxazaphosporine; anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation (very low
activity) activation to
cytotoxic metabolites		 activation 253 10348794
CYP3A5 drug estradiol derivative; estrogen,
contraceptive		 17α-ethynylestradiol
(ethinylestradiol,
17α-)		 oxygenation (2-
hydroxylation, 17α-
mechanism-based
inactivation)		 activation 140, 348 17584015,
17251390
CYP3A5 drug antimitotic, epipodophyllotoxin,
topoisomerase II inhibitor		 etoposide (VP-16) O-demethylation (catechol
formation), medium Km, high
activity, minor enzyme		 activation 349 8114683
CYP3A5 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation,
stereoselective for (R)-		 activation 253, 276,
277, 353, 355 		10348794,
10534317,
15821045,
10101149,
16854777
CYP3A7 drug oxazaphosporine; anticancer, nitrogen
mustard, alkylating		 cyclophosphamide C4-hydroxylation activation 253, 275 10348794,
15919850
CYP3A7 drug oxazaphosporine; anticancer, nitrogen
mustard alkylating		 ifosfamide C4-hydroxylation
stereoselective for (R)- (high
Km, medium (S-) and high
(R-) activity, minor enzyme
and reaction)		 activation 253, 275 10348794,
15919850
Lactoperox
idase
(LPO) 		drug pyrido-carbazole; antineoplastic,
alkaloid, Apocyanaceae plants
compound, topoisomerase II inhibitor
and DNA binding		 Ellipticine oxidation activation 39, 40 16936898,
21753906
Myelopero
xidase
(MPO) 		drug pyrido-carbazole; antineoplastic,
alkaloid, apocyanaceae plants
compound, topoisomerase II inhibitor
and DNA binding		 ellipticine oxidation activation 39, 40 16936898,
21753906
NADPH-
cytochrom
e P450
reductase
(POR) 		drug dihydroxyanthraquinone, laxative danthron reduction activation 385 11697035
SULT1A1 drug triphenylethyleneamine; antiestrogen,
estrogen receptor modulator,
metabolite		 4-hydroxytamoxifen O-sulfonation activation 402, 403 12034366,
21537383
SULT2A1 drug pregnane, antiandrogen, metabolite 3α-
hydroxycyproterone
acetate		 O-sulfonation activation 394 11535246
SULT2A1 drug triphenylethyleneamine; antiestrogen,
estrogen receptor modulator,
metabolite		 α-hydroxytamoxifen O-sulfonation activation 412, 413 9855017,
15371299
SULT2A1 drug thioxanthenone, schistosomicide hycanthone O-sulfonation potent
activation		 394, 395 11535246,
9141497
SULT2E1 drug thioxanthenone, schistosomicide hycanthone O-sulfonation activation 394 11535246
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The classification of compounds into Tables 2 and 3 is somewhat arbitrary. Most of the data on activation of carcinogenic chemicals is with “chemicals” and only a limited amount with drugs and physiological compounds/natural products. We selected some compounds found in nature that are known to be carcinogens under some conditions, e.g. estrogens. Natural products are included (although one could also consider the PAHs to be natural, too). The set of drugs is mainly those used to treat cancer by DNA alkylation, topoisomerase poisons, etc. These compounds are often tumorigenic themselves and have been included. The term “chemicals” is used to describe these components that do not fit well into the natural product or drug classification. Even here there is room for change, e.g. many of the nitrosamines can be formed from secondary amines in vivo.

Another point that should be made is that we use the term carcinogen broadly, including some compounds that are “cancer suspects” and might have caused cancer at very high doses in experimental animal models. Inclusion in the tables here does not necessarily carry an endorsement as a human carcinogen for any regulatory purposes. Some of the compounds cited here are used effectively as drugs, and some are physiological compounds known to be important in normal homeostasis, e.g. estrogens.

The analysis of greatest interest is the activation of chemical carcinogens, and the results are summarized in Figure 2 as well as in Table 1, the main point of this review. The most striking aspect is the dominant role of the P450 enzymes. Interestingly, beyond these the AKR enzymes have a role that exceeds that of any other enzyme group, driven by their reported roles in PAH activation to quinones.485

Of the P450s, six P450s—1A1, 1A2, 1B1, 2A6, 2E1, and 3A4—account for 77% of the reported activations (Figure 2B). The Family 1 enzymes are prominent in the activation of PAHs and heterocyclic aromatic amines, plus arylamines and a variety of other compounds. The values for P450s 2A6 and 2E1 are driven by their roles in the metabolism of N-nitrosamines and a variety of low Mr commodity chemicals, including several vinyl monomers.282

INTERPRETATIONS OF THE ASSIGNMENT RESULTS

Activation vs. Detoxication

We have presented separate tables for activation (Tables 1-3) and detoxication of carcinogens (Table 4). However, distinguishing a role for an enzyme in this regard may be difficult. E.g. there is the classic case of the action of epoxide hydrolase in benzo[a]pyrene activation (Figure 3).486 Another example has a single enzyme forming two different products from the same substrate, the P450 3A4-catalyzed oxidation of AFB1 to AFQ1 (3-hydroxylation, detoxication) and AFB1 8,9-exo-epoxide (activation) (Figure 4).176 The activation of the anticancer drug ellipticine is catalyzed by cyclooxygenases, peroxidases, and P450 enzymes (Tables 1, 2). Hydroxylations at positions C12- and C13, as well as N2-oxidation, are associated to the activation of ellipticine to toxic metabolites. These reactions are catalyzed mainly by the P450 1A1, 1A2, 1B1, and 3A4 enzymes. The same P450 enzymes catalyze detoxication of ellipticine by hydroxylation at the C7- and C9-positions, and the major enzymes considered are P450s 1A1 and 1A2 (Table 4). It has been reported that the balance of activation vs. deactivation of this drug is dependent on cytochrome b5, in that cytochrome b5 enhances production of 12-hydroxy and 13-hydroxyellipticine and thus changes the product ratio in a favor of increased formation of covalent ellipticine-DNA adducts. The effect of cytochrome b5 might be even more pronounced in vivo, in that it has been reported that ellipticine increases levels of cytochrome b5 in rat liver.39,187,189

Figure 3.

Figure 3

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Diol-epoxide pathway of benzo[a]pyrene activation.486

Figure 4.

Figure 4

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Oxidation of AFB1 by P450 3A4.176

Another issue involves tissue selectivity. As a case in point, GSH transferases catalyze the conjugation of bifunctional electrophiles (e.g., ethylene dibromide, Figure 5) with GSH to form half-mustards and then episulfonium ions.377 These reactive species can react with DNA and are considered to be involved in chemical carcinogenesis. However, if such reactions occur in erythrocytes there is no DNA and this might be considered a detoxication.

Figure 5.

Figure 5

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Conjugation of ethylene dibromide with GSH.377

Selectivity of activation vs. detoxication reactions is observed in the acetylation of N-hydroxy heterocyclic and aromatic amines (Table 1 vs. Table 4). The vast majority of heterocyclic amines do not undergo detoxication by N-acetylation because most heterocyclic amines are poor substrates for NATs. These compounds do undergo bioactivation by NATs via O-acetylation, following P450-mediated N-oxidation of the exocyclic amine groups. In contrast to heterocyclic amines, many aromatic amines do undergo detoxication by N-acetylation with NATs.

As mentioned before, chemical carcinogens are activated by a number of enzymes, of which the major ones are P450, SULT, AKR, and NAT (Figure 2 and Table 2), while the data on activation of natural/physiological compounds show that primarily P450 (92%, of which the major ones are 1A1, 1A2, 1B1, and Subfamily 3A) and SULT (8%) enzymes participate in their activation (Table 3). Similarly to general chemicals, drugs are activated by P450s (76%), SULT (12%), LPO (7%), and COX (5%) enzymes. Major P450 enzymes assigned are 3A4 (20%) and 1A2 (11%), and participation of others is low (Table 2).

When considering activation vs. detoxication reactions for a specific compound and/or reaction, attention should be given to the experimental conditions applied and the properties of the compounds and metabolites formed. For instance, 2-nitroanisole is (under oxidative conditions) detoxicated by C2-, C5-, and C6-hydroxylations catalyzed by P450 2E1, 1A1, and 2B6 enzymes (2E1 being the major one). However, under anaerobic conditions activation by nitroreduction prevails due to catalysis by XOR. In addition, 2-nitroanisole and its metabolite 2-nitrophenol induce P450 1A2 and NQO1 (in rats), thus providing the possibility to influence their own detoxication and/or activation pathways.423,424

Our approach here has been to list enzymes under both activation and detoxication in cases that are deemed to be duplicative.

Influence of the Diversities of Different Chemical Classes

In making the assignments shown in Figure 2, the number of compounds available can be considered a contributor to the reported results. For instance, it is known that P450s 1A1 and 1B1 (and AKR enzymes) can oxidize many PAHs.220,485,486 Many of these are available, given the long-standing interest in individual PAHs,4 and have been tested with P450s.41,109,229 Likewise, many arylamines and heterocyclic aromatic amines are known and have been tested with P450 1A2.12 Further, many N-nitrosamines (and vinyl monomers) have been tested with P450s 2A6 and 2E1.247,282 It is possible that, in the future, the availability of a large number of analogs in another class of carcinogens might lead to more testing and shift the balance of the results in Figure 2.

Another point to be made here is that our classification includes compounds shown to be pro-mutagens, to bind covalently to DNA, etc. We do not have evidence that all of the compounds listed in our tables actually cause tumors in experimental animals or humans, although we believe that there is a likelihood that they do at some dose (readers are referred to the National Toxicology Program, International Agency on Cancer Research, and other sources for in vivo cancer results and classifications of human carcinogens).

Types of Reactions

Another analysis involves the type of reactions involved in bioactivation reactions (Figure 6). As seen there, 11 reactions account for 94% of the total, each representing 5-12%. The O-acetylation and O-sulfonation conjugation collectively account for 18%. Nitroreductions (6%) plus other reductions (0.3%) constitute 6.3%. Most of the other reactions are oxidations, together accounting for ~ 73%. Of these, N-hydroxylation (10%) and C-hydroxylation (11%) are the most prominent.

Figure 6.

Figure 6

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Analysis of types of activation reactions (data of Table 1, total of 799 reactions). See text for discussion.

The results support the general view that there are many ways to activate procarcinogens (Figures 1, 3-5). As with the classification by enzymes (vide infra) there are caveats about representation based on the number of compounds experimentally available.

We have not analyzed the entries in Table 1 in the context of the chemical nature of the substrate, but this is rather obvious from the nature of Figure 6. Epoxidations involve olefins and aryl rings, nitro reductions involve nitro groups, N-hydroxylations involve arylamines and heterocyclic amines (O-acetylation involves the products), and O-sulfonation involves hydroxylarylamines and benzylic allylic alcohols. Cα-Hydroxylation is prominent for N-nitrosamines. Thus, a single group of chemicals does not dominate.

Weaker Activations

Several enzymes and their reactions have been included in the analyses, although the evidence for significance of their roles in rather weak. There was not a logical reason to delete these from our analysis nor a means of setting a strict benchmark for strong vs. weak roles because of the diversity of assays used. Further, “weak activation” (included in Table 1) might become “activation” or “potent activation” either following ingestion of certain enzyme inducers and/or the expression of a more active variant of the enzyme, as exemplified in several animal models.27

In this regard, we had reported a major role for P450 2C9 in benzo[a]pyrene 3-hydroxylation in human liver.430 Although this reaction has been studied for many years and is the basis of the classic “AHH” activity,487 it is generally not considered to be a bioactivation process, especially in liver. P450 enzymes such as those in the P450 2D6 and Subfamily 2C have been tested for several activities and do have low levels of activity (Table 1), but there is little if any evidence that these drug-metabolizing enzymes have major roles in chemical carcinogenesis in humans.

Similar points can also be raised about the activation of AFB1. Although a number of forms of human P450 have some capability of activating AFB1 (Table 1),139 the evidence is very limited that most of these have relevance. The established target of AFB1 in the liver, and enzymes that are predominantly expressed in other tissues are not very relevant. The existing literature clearly shows roles of primarily two P450s, 3A4 and 1A2.432,443,488 P450 3A4 forms the highly mutagenic exo-8,9-poxide; P450 1A2 forms a roughly equimolar mixture of the dangerous exo-plus the endo-epoxide, the latter of which is essentially non-genotoxic.176,432,489 The situation is complicated in that both of these enzymes also catalyze AFB1 detoxication reactions, 3α-hydroxylation in the case of P450 3A4 (AFQ1) and 9a-hydroxylation in the case of P450 1A2 (AFM1).176

The information presented in this review is relevant in the context of translational studies. A case in point involves P450 2D6 and lung cancer. The interest began even before the characterization of P450 2D6, with a report that individuals with lung cancer showed a low representation of phenotypically poor metabolizers of debrisoquine, subsequently confirmed as a P450 2D6 prototypic substrate.490 These results led to the consideration of the hypothesis that P450 2D6 is involved in the bioactivation of a major carcinogen leading to lung cancer. The level of P450 2D6 in lung tissue is low,491 but it is conceivable that systemic exposure to an entity produced in the liver could be involved. However, attempts to identify a major role of P450 2D6 in the activation of carcinogens have been resoundingly negative.492,493 Further, studies on the genotoxicity of crude cigarette smoke condensates and liver microsomes showed a role for P450 1A2 but not P450 2D6, based on the use of inhibitors etc.149

An alternate hypothesis, given the lack of evidence for a role of P450 2D6 in bioactivation of carcinogens, is that the CYP2D6 gene is linked to the expression of an oncogene. However, no evidence for this hypothesis exists and the known major genetic defect regulating P450 2D6 is aberrant RNA splicing, which is not likely to involve co-regulation of nearby genes.494 Additional epidemiology studies have generally not confirmed a major effect of P450 2D6 expression related to any kind of lung cancer.495,496 In our opinion, resources could be used more effectively if sound experimental studies preceded expensive epidemiological studies with marginal bases of biological causality.

Analysis of Enzymes Involved in Detoxication

Analysis of the data on detoxication is presented in Figure 7. GST and UGT reactions account for > 50% of the reactions, which is not surprising. Two other transferases, NAT and COMT, are also prominent. The fraction attributed to AKR reactions is surprisingly high. Also surprising is the low fraction attributed to epoxide hydrolase, which seem surprising in light of the notoriety of epoxides in toxicology and drug metabolism circles.497 However, epoxide hydrolase is rather ineffective in hydrolyzing some of the most reactive epoxides498 and AFB1 8,9-epoxides.433 However, the roles of epoxide hydrolase and sulfotransferases in detoxication may be underestimated because of the nature of the reactions that have been reported to date with the human enzymes. We suspect that there is more literature using animal epoxide hydrolases that has not been re-done with the human enzymes, and the overall picture (Figure 7) might be misleading. The results of Figure 7 can be contrasted with those in Figures 2 and 6, when the SULT enzymes figure in many bioactivation reactions. However, judging sulfotransferases to be primary bioactivation enzymes, as opposed to detoxication, may not be a proper conclusion. P450s are involved in ~ 14% of the detoxication reactions with carcinogens (Figure 7), but this estimate may not be accurate. As with all of the enzymes of interest here, the assays for bioactivation (e.g. Ames test, umu assays, covalent binding) are often easier to set up than those that would accurately measure detoxication, and the literature may be misleading as to the relative importance of the detoxication enzymes.

Figure 7.

Figure 7

Figure 7

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Analysis of detoxication reactions. A: Enzymes involved in detoxication. B: Reactions involved in detoxication. Data are from Table 4 (total of 281 reactions). See text for discussion.

Potential Roles of “Orphan” Enzymes

The analysis of enzymes and P450s (Figure 2) is based on existing knowledge (of the enzymes, as well as the carcinogens), and the pattern might change with time. With the (human) P450s, ~ 1/4 can still be considered “orphans,” in the sense that limited information is available about their catalytic activities and their roles in physiological processes.499 Further, only limited information is available about roles in carcinogen metabolism. An exception in this regard is P450 2W1, which has been shown (like P450 1B1) to activate several classes of carcinogens.210 Of interest is the reported expression of P450 2W1 only in tumor tissue.500 Another orphan P450, P450 4F11, was found not to have appreciable activity towards any carcinogens tested.501

The role of P450 2S1 in the activation of carcinogens is controversial, as well as almost all other potential substrates. Following the initial discovery of human P450 2S1,502 it was reported that the enzyme would oxidize naphthalene.503 However, this report was not confirmed and no evidence for a role of P450 2S1 in the activation of any carcinogens was seen.210 Further, the only substrate reported and independently confirmed for P450 2S1 is the drug candidate 1,4-bis{[2-dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione (AQ4N).504,505 Some carcinogens can be activated by P450 2S1 in the presence of oxygen surrogates (hydroperoxides)506,507 but the significance of these reactions is unknown, in that P450 2S1 has been demonstrated to be rapidly reduced by NADPH-P450 reductase in the usual manner.505 Nevertheless, expression of P450 2S1 in a mammalian cell line did lead to the formation of products of benzo[a]pyrene, indicating some mechanism of function.506,507

A number of the other P450 orphans have been expressed508 but apparently roles in carcinogen metabolism have not been investigated. This same statement can be applied to other enzymes under consideration, regarding recently discovered gene products.

We should point out that our analyses are based largely on studies done with the “wild type,” or most abundant genetic variants, in the human population. A treatment of all of the implicaitons of variations is beyond the scope of this review and indeed the catalytic efficiencies of only a subset of the variants of these enzymes has been determined with any substrates (e.g., http://www.cypalleles.ki.se/) and few with carcinogens. However, if a racial group exists in which the frequency of a fuctional polymorphism is high, then the balance of enzyme involvement (e.g., Figure 2B) could be shifted.

COMPARISONS OF PATTERNS FOR THE METABOLISM OF DRUGS AND CARCINOGENS

We25,509-512 and others22-24 have presented compilations of the roles of P450s and other enzymes involved in the metabolism of drugs. Comprehensive and up-to-date information on the metabolism of chemicals (including drugs and physiological compounds) in humans and animal models is available in a form of Web searchable absorption-distribution-metabolism-excretion (ADME) database (http://jp.fujitsu.com/group/kyushu/en/services/admedatabase/). The generally accepted view is that, for the drugs that undergo metabolism, almost 75% involve P450 reactions.23-25 Five P450s—1A2, 2C9, 2C19, 2D6, and 3A4—are involved in ~ 90% of these P450 reactions.23-25 This situation, i.e. a large segment of drug metabolism being controlled by a few enzymes, has been useful in being able to rapidly define metabolism issues in drug development.

In an analysis made previously with a total of 7906 entries (metabolic reactions catalyzed by P450s with different compounds as substrates),513 2065 entries are related to P450 Subfamily 3A enzymes, i.e. 26% of the total. Making similar analysis for clinically significant drugs,513 P450 3A4 and 3A5 enzymes participated in 34% of the total P450-catalyzed metabolic reactions, less than the ~50% presented by others.23,24 The contribution of the P450 Subfamily 3A enzymes may be overestimated, or the differences may reflect the time period sampled or the possible differences between sets of drugs published in the open literature vs. proprietary drugs and those in development used in the analyses.

The results shown in Figure 2 can be compared to drug metabolism. The first point is that a similar fraction of the total bioactivation (68%) is due to P450 enzymes (Figure 2A). The five P450s involved in drug metabolism are “replaced” with six—1A1, 1A2, 1B1, 2A6, 2E1, and 3A4—that collectively account for 77% of the P450-mediated reactions.

The numbers resulting from the present analysis of updated earlier data513 on all compounds fit better to the data we report in the activation of the carcinogens by human P450s, and can be used for comparisons. E.g., participation of P450s 1A1, 1A2 and 2E1 in carcinogen activation reactions is 20, 17, and 11%, respectively, and their participation in total metabolic reactions presented here is 7, 10, and 5%, respectively. The participation of P450 1B1 in activation is 11%, and in total metabolism reactions is 3%. However, the participation of P450 3A4 in activation reactions is 10% and its participation in all metabolic reactions is 20%.

The participation of P450 2C9 in activation reactions is ~2% and in total metabolism reactions is 9%; the participation of P450 2C19 in activation reactions is 1% and in total metabolism reactions is 8%. Finally, the apparent participation of P450 2D6 in activation reactons is ~2% and in total metabolism reactions is 10%. We make the general conclusion that the contribution of “toxicologically significant” enzymes (e.g. P450s 1A1, 1A2, 1B1, 2A6, 2E1) is greater in activation reactions and less in considerations of total metabolism. The opposite is the case for generally-detoxicating enzymes, e.g. P450s 2D6, 3A4 (with exceptions), and the 2C Subfamily.

APPLICATIONS

The information presented here is intended to provide a summary to readers who are interested in the literature on human enzymes involved in chemical carcinogenesis reported to date. Further, the analyses (Figure 2) have uses in themselves, despite the stated caveats, in evaluating the individual enzymes.

The analysis provides some guidance in translational applications. For instance, the information presented in Figure 2 can direct the efforts of those in the field of molecular epidemiology of cancer as to which genes and single nucleotide polymorphisms might be most profitable to study. Likewise, some guidance is provided to those in the field of chemoprevention as to which enzymes and reactions might be most useful to inhibit or induce. Such considerations also apply in general issues of risk assessment, in evaluating issues such as inducibility and inter-individual variation.

The analysis (Figure 2) is also useful in basic research. For one thing, it was a matter of curiosity for us—after studying the area for so long513—to know which P450s are most prominent in chemical carcinogenesis. Thus, justification is clearly provided for studying the six P450s cited in Figure 2B (1A1, 1A2, 1B1, 2A6, 2E1, 3A4). Of the six, only P450 1A1 has not been reported at the level of a crystal structure. However, none of these P450 structures has been solved with a carcinogen bound. An overall hope is to use our knowledge of structure-activity relationships to predict which new chemicals will be activated and whether products will be toxic or carcinogenic. In addition, there are numerous basic questions regarding how P450s, including those cited here, such as: What is the molecular basis of catalytic selectivity? What factors determine rates of particular P450 reactions? What is the molecular basis of the cooperativity seen in P450s, including some of those described here, e.g. P450 3A4 and also P450 1A2 (with pyrene).514

It should be emphasized again that almost all of the work cited here was done in the past 25 years.27 In dealing with an effort of this scope, we might have overlooked some useful papers in the field and apologize to those authors in advance. An Excel file of an expansion of Table 1 is included for the ease of those readers who wish to search it or use it to develop or update their own databases.

Supplementary Material

1_si_001

ACKNOWLEDGEMENT

We thank L. M. Folkman and particulary K. Trisler for assistance in preparation of the manuscript. We also acknowledge the pioneering efforts of Dr. Frederick J. DiCarlo and his contributions to the area of xenobiotic metabolism. This review is dedicated to the memory of two eminent cancer researchers who passed away recently, Drs. Fred F. Kadlubar and Donald M. Jerina. Both played major roles in the work summarized here and are missed in this field.

FUNDING SOURCES

This study was supported in part by National Institutes of Health grants R37 CA090426 and R01 ES010546 (F.P.G.).

ABBREVIATIONS

AF

aflatoxin

AGT or MGMT (used in tables)

O6-alkylguanine DNA-alkyltransferase

AKR

aldo-keto reductase

COX (used in tables) or PTGS

cyclooxygenase (prostaglandin synthase)

P450 or CYP (used in tables)

cytochrome P450

FMO

microsomal flavin-containing monoxygenase

GST

glutathione (GSH) transferase

HAA

heterocyclic arylamine

NAT

N-acetyltransferase

NPR or POR (used in tables)

NADPH-P450 reductase

NQO

NADPH-quinone reductase

PAH

polycyclic aromatic hydrocarbon

SULT

sulfotransferase

UGT

UDP glucuronosyl transferase

XOR

xanthine oxidoreductase

Footnotes

Footnote 1: For convenience we will use the term “carcinogens” to refer to both carcinogens that act directly (e.g., modifying DNA) and to procarcinogens (i.e., those that require metabolism to be converted to act on biological targets). In the tables the term “chemicals” is used for those chemicals that are not drugs or natural products.

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