Table 10.

P450 19A1

Properties	References
Physiological substrates: Testosterone, androstendione, 16α-androstendione, 16β-OH-androstenedione, 17β-estradiol, dihydrotestosterone	(Zharikova et al. 2007; Pan et al. 2016;Ghosh et al. 2018;Magistrato et al. 2017;Neunzig et al. 2017)
Other substrates:
Drugs: L-α-Acetylmethadol, methadone, buprenorphine, tiboline, nortestosterone (norethisterone)
Sex hormone derivatives: 7α-Methyl-19-nortestosterone (trestolone), androst-5-ene-4,17-dione, androstadiene-3,17-dione, androst-4,6-diene and −1–4-diene-3,17-diones, 6-alkyl- and 6-ether analogs
Other compounds: Dibenzylfluorescein, 7-methoxy-4-trifluoromethylcoumarin, 6α-methoxyandrost-1,4-diene-3,17-dione dervatives
Inhibition: Lowered estrogen levels in breast and endometrial cancers, decreased estradiol secretion, anti-androgen activity (Vanden Bossche et al. 1994; Lønning and Eikesdal 2013; Ahmad and Shagufta 2015; Linardi et al. 2017; Kang et al. 2018)
Inhibitors: (Yumoto et al. 1976; Zhou et al. 1990; Kelloff et al. 1998; Ahmed and Amanuel 2000; Seralini and Moslemi 2001; Conley et al. 2002; Lønning and Eikesdal 2013; Bois et al. 2017;Sgrignani et al. 2014;Punetha et al. 2011;Caporuscio et al. 2011;Hirani et al. 2004; Hadizadeh et al. 2018)
Drugs :
Aminoglutethimide a (Ayub and Levell 1988; Kitawaki et al. 1990; Zhou et al. 1990; Campbell and Kurzer 1993; Wang C et al. 1994; White et al. 1999)
Antiepileptic drugs b (lamotrigine, tiagabine, oxcarbazepine, phenobarbital, phenytion, ethosuximide, valproic acid) b (Jacobsen et al. 2008; Glister et al. 2012; Chen Y et al. 2015)
Cyclooxygenase-1 selective inhibitors c (SC-560) (Brueggemeier et al. 2005; Diaz-Cruz et al. 2005)
Cyclooxygenase-2 selective inhibitors c (celecoxib, niflumic acid, nimesulide, NS-398 and N-methyl anolog, SC-58125) (Brueggemeier et al. 2005; Diaz-Cruz et al. 2005; Su et al. 2008)
15-Deoxy-prostaglandin J2 (15-dPGJ2) b (Andrews et al. 2005)
Exemstane d and derivatives (Görlitzer et al. 2006; Hong et al. 2007; Lønning and Eikesdal 2013; Kümler et al. 2016; Chottanapund et al. 2017)
Fenretinide b (Andrews et al. 2005)
Formestane b (Pokhrel and Ma 2011)
Fulvestrant (Kümler et al. 2016)
Fungicides, imidazoles e (e.g., bifonazole, fadrozole, tioconazole, clotrimazole; anastrozole, econazole, miconazole, isoconazole, ketonazole, letrozole, tinidazole (weak inhibitor), carbimazole (weak inhibitor), metronideazole (weak inhibitor), econazole, miconazole, mebendazole, thiabendazole (weak inhibitor), nimorazole (weak inhibitor), astemizole (weak inhibitor), mebendazole (weak inhibitor), propiconazole, (Ayub and Levell 1988, 1990; Ahmed et al. 1995; Sanderson JT et al. 2002; Zarn et al. 2003; Sanderson JT et al. 2004; Trösken et al. 2004; Trösken, Fischer, Volkel, et al. 2006; Kjeldsen et al. 2013; Lønning and Eikesdal 2013; Linardi et al. 2017;Di Nardo et al. 2018;Magistrato et al. 2017)
Metformin c (Takemura et al. 2007; Rice et al. 2009)
Non-steroidal anti-inflammatory drugs c (ibuprofen, piroxicam, indomethacin, nimesulide) (Brueggemeier et al. 2005)
Norendoxifen (tamoxifen metabolite) b (Lu WJ, Desta Z, et al. 2012; Lu WJ, Xu C, et al. 2012)
Opiates a (sufentanil, L-acetylmethadol, methadone, EDDP, (nor)buprenorphine, Oxycodone (weak inhibitor), codeine (very weak inhibitor)
Pentazocine (very weak inhibitor) (Zharikova et al. 2006; Zharikova et al. 2007)
Plomestane d (19-acetylenic androstenedione) (White et al. 1999)
Rifampicin a (Kim et al. 2013)
Rogletimide b (Vanden Bossche et al. 1994)
Tamoxifen, raloxifene b (Fiorelli et al. 1999)
Testolactone b (low potency inhibitor) (Dunkel 2006)
Tiboline, ∆4,7α-methyl norethisterone metabolite a (Raobaikady et al. 2007)
Tibolone and its ∆4, 7α-methyl norethisterone metabolite b (Raobaikady et al. 2007)
Troglitazone plus LG100268 c (Mu, Yanase, Nishi, Waseda, et al. 2000; Yanase et al. 2001)
Natural compounds;
Alkylresorcinols c (Oskarsson and Ohlsson Andersson 2016)
Cree plant extracts b (Tam et al. 2009)
Cicer arietinum seeds extracts b (Zhang et al. 2018)
Depsidones b (unguinol and aspergillusidone A) (Sureram et al. 2012; Chottanapund et al. 2017)
Flavonoids, polyphenols, chalcones c (e.g., biochanin (potent inhibitor), butein, 4-hydroxychalcone, 8-prenylnaringenin, apigenin (at high doses), quercetin (at high doses), genistein (at high doses—or no inhibition), baicalein, biochanin A (at high doses), daidzein (at high doses), naringenin (potent inhibitor), chrysin (potent inhibitor), coumestrol, rotenone (potent inhibitor), luteolin, kaempferol, 7,8-benzoflavone, 7-hydroxyflavones, 7-hydroxyflavanone, 4´-hydroxyflavanone, 7,4´-dihydroxyflavone, flavone (weak inhibitor), flavanone (weak or no inhibition), quercetin (weak inhibitor), genistein 4´-methyl ether (weak inhibitor), formononetin (also no inhibition) (Kellis J.T., Jr. and Vickery 1984; Ibrahim and Abul-Hajj 1990; Campbell and Kurzer 1993; Wang C et al. 1994; Le Bail et al. 1998; Fiorelli et al. 1999; Jeong et al. 1999; Le Bail et al. 2000; Le Bail et al. 2001; Saarinen et al. 2001; Vinh et al. 2001; Almstrup et al. 2002; Sanderson JT et al. 2004; Lacey et al. 2005; Wang Y et al. 2005; Rice et al. 2006; van Meeuwen et al. 2007; van Meeuwen et al. 2008; McNulty et al. 2009; Lu DF et al. 2012)
(−) Gossypol b (Zhong et al. 2010; Dong et al. 2016)
Green tea extract catechins b (Satoh et al. 2002)
Isodon excisus var. Coreanus b (Jeong et al. 2000)
Isoflavone derivatives b (Su et al. 2005)
Lignans b (nectandrin-B) (Filleur et al. 2001)
Lignans b (lignan, O-demethylsecoisolariciresinol, demethoxysecoisolariciresinol, didemethylsecoisolariciresinol) (Adlercreutz et al. 1993; Wang C et al. 1994)
Melatonin, resveratrol b (Chottanapund et al. 2014)
Phytoestrogens c (Le Bail et al. 2000; Whitehead and Lacey 2003; Lacey et al. 2005)
Phytoestrogens b (chrysin, biochanin A, naringenin, formononetin; at low concentrations) (Almstrup et al. 2002)
trans-Phytol (SA-20), (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48) c (Guo et al. 2014)
Red wine exctract b (procyanidin B dimers, resveratrol) (Eng et al. 2001, 2002; Eng et al. 2003; Wang Y et al. 2006; Wang Y and Leung 2007; Linardi et al. 2017)
Sesquiterpene lactones a (guaianolides 10-epi-8-deoxycumambrin B, dehydroleucodin, ludartin (Blanco et al. 1997)
UVA-ursi herbal products b (Chauhan et al. 2007)
White button mushroom phytochemicals b (Grube et al. 2001; Chen S et al. 2006)
Yikun neiyi wan c (Wang Q et al. 2009)
Zaraleone b (Lacey et al. 2005)
Physiological compounds:
17β-Estradiol c (in women) (Dieudonné et al. 2006)
4-Hydroxyandrostendione f (Abul-Hajj 1983; Ayub and Levell 1988, 1990; Zhou et al. 1990; White et al. 1999; Vinggaard et al. 2000; Almstrup et al. 2002; Numazawa et al. 2002)
Leptin c (in women) (Dieudonné et al. 2006)
Physiological condition:
Hypoxia c (Jiang et al. 2000; Jiang and Mendelson 2005)
Other compounds, including drug candidates:
(±)-Abyssinone II and analogues b (Maiti et al. 2007)
7-(α-Azolylbenzyl)-1H-indoles and indolines b (Marchand et al. 2003)
4-(Aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives b (Ertas et al. 2018)
3–(1H-imidazol-1-yl)-2H-chromen-2-one a (Niinivehmas et al. 2018)
Atrazine c (Pogrmic-Majkic et al. 2018)
1-[(Benzofuran-2-yl)(phenylmethyl)pyridine, -imidazole, and -triazole inhibitors b (Saberi et al. 2006)
Bisphenol A, lindane b (longer incubation time, up to 18 h) (Almstrup et al. 2002; Nativelle-Serpentini et al. 2003; Benachour et al. 2007; Chu et al. 2018)
4´-tert-Butyl-quinolin-4-one b (Sanderson JT et al. 2004)
C19 steroidal 17-oxime analogs b (Pokhrel and Ma 2011)
Carbon black nanoparticles b (Simon et al. 2017)
Chlordecone b (Benachour et al. 2007)
Cinnamyl triazoles b (McNulty et al. 2014)
Dibutyl phthalate c (Mauger 1989)
Diethylstilbestrol b (Benachour et al. 2007)
N,N-Disubstituted-5-aminopyrimidine derivatives b (Okada et al. 1997)
Estrone and estradiol derivatives (2-, 4-, or 6-substituted) b (Numazawa et al. 2005)
19-(Ethyldithio)-androst-4-ene-3,17-dione (OrG 30958) b (Geelen et al. 1991)
Fungicides b (prochloraz, imazalil, flusilazole, fenbuconazole, propioconazole, difenoconazole, penconazole, fenarimol, triadimenol, triadimefon, toxaphen, heptachlor, dicofol, ziram, vinclozolin, tributyltin oxide, myclobutanil) (Vinggaard et al. 2000; Heneweer et al. 2004; Trösken et al. 2004; Laville et al. 2006; Trösken, Fischer, Völkel, et al. 2006; Benachour et al. 2007; Chen L et al. 2017)
Herbicides b (atrazine) (Benachour et al. 2007)
ICI 182,780 c (Almstrup et al. 2002)
5-Hydroxy-BDE47, 6-hydroxy-BDE47, 6-hydroxy-BDE99) b (Cantón et al. 2005; Cantón et al. 2008)
Imidazole,triazole and pyridine based compounds b (Ahmed et al. 1995; Saberi et al. 2006)
1-(1H-Imidazol-1-yl)methyl-6-chloro-9H-xanthen-9-one, lactones (CRI-7, 8, and 9)
Insecticides b (dieldrin, toxaphenem)(Almstrup et al. 2002; Laville et al. 2006)
Lactone derivatives b (Sanderson T et al. 2008)
MDL 18,962 d (19-acetylenic androstenedione, and analogs) (Johnston et al. 1990)
4-Methoxy-androst-4-ene-3,17-dione (White et al. 1999)
2-Methoxyestrone-3-O-sulfamate b (Purohit et al. 2005)
Mono-(2-ethylhexyl) phthalate f (Noda et al. 2007)
Nonylphenol b (Almstrup et al. 2002; Benachour et al. 2007)
α-Naphthoflavone and derivatives b (Kellis J. T., Jr. et al. 1986; Campbell and Kurzer 1993; Sanderson JT et al. 2004)
Organochlorines c (e.g. TCDD, PCB126) (Drenth et al. 1998; Letcher et al. 1999)
Pesticides b (prochloraz (IC(50) <1 μM), fenbuconazole (IC50 1.1 μM), propiconazole (IC50 1.5 μM) fenarimol (IC50 3.3 μM); toxaphen (10 μM) and heptachlor (10 μM) only after 24 h exposure), epoxyconazole, endosulfan (weak inhibitor) (Andersen et al. 2002; Heneweer et al. 2004; Laville et al. 2006)
Pesticides j (i-butyl-, tributyl-, and triphenyltin chloride) (Sanderson JT et al. 2002; Benachour et al. 2007)
Pesticides j (p,p´-DDT, o,p´-DDT, p,p´-DDE, o,p-DDE) (Sanderson JT et al. 2002; Wójtowicz et al. 2007)
Polybrominated diphenyl ethers, brominated flame retardants b, (e.g., 2-hydroxy-BDE, 2,4,6-tribromophenol, 5-hydroxy-BDE47, 6-hydroxy-BDE47, and 6-hydroxy-BDE9) (Cantón et al. 2005; Cantón et al. 2008)
Polychlorinated biphenyls c (Aroclor 1254, PCB39) (Benachour et al. 2007; Li 2007)
Protein kinase inhibitors PD98059, KN-93m H-89 b (Watanabe et al. 2006)
2-Pyridinyl-substituted γ-naphthoflavones (at concentrations >30 μM) b (Sanderson JT et al. 2004)
Pyridine-substituted thiazolylphenol derivatives (non-steroidal triazole bioisosteres) b (Ertas et al. 2018)
Pyridoglutethimide a (Kitawaki et al. 1990)
Pyridyl-substituted indanones, indans, and tetralins b (Hartmann et al. 1994)
Pyridyl-substituted tetrahydrocyclopropa[a]naphthalenes b (Hartmann et al. 1995)
Ro41–5253 f (RARα-selective antagonist) (Hartmann et al. 1995)
RU486 c (antiglucocorticoid and antiprogestin) (Schmidt and Löffler 1997)
Steroidal derivatives d (6-oxoandrostenedione and its 19-hydroxy analog, 10α-acetoxyestr-5-ene-7,17-dione, androst-5-ene-4,7,17-trione, and 17α-ethynyl-19-nortestosterone) (Hartmann et al. 1995; Numazawa and Yamaguchi 1998; Numazawa et al. 1998; Numazawa and Yamada 1999; Numazawa and Yamaguchi 1999; Numazawa et al. 2000; Numazawa et al. 2002; Numazawa et al. 2003)
Sulfonanilide analogues c (Su et al. 2006)
Synthetic lactones (TM-7, TM-8, TM-9 b (Cantón et al. 2008)
Thioglutethimide derivatives a (Bednarski and Hartmann 1993)
Triazole derivatives e (CGS 20267, CGS 47645, R 76 713, ICI D1033) (Vanden Bossche et al. 1994)
Triazolylflavans b (Yahiaoui et al. 2004)
Induction: Over-expression associated with increased risk of developing estrogen-dependent mammary tumors
Inducers:
Drugs:
Dexamethasone g (Zhao et al. 1996; Heneweer et al. 2004; Enjuanes et al. 2005; Watanabe et al. 2005)
Insulin h (Rice et al. 2006)
Mibolerone i (Stillman et al. 1991)
Opiates g (morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, (−)-pentazocine, naloxone, naltrexone, sufentanil) (Zharikova et al. 2007; Cui et al. 2011)
Pacitaxel (taxol) i (Morinaga et al. 2004)
Natural compounds:
1α,25-Dihydroxyvitamin D3 (calcitriol) i (Yanase et al. 2003; Enjuanes et al. 2005; Lou et al. 2005; Pino et al. 2006; Barrera et al. 2007)
All-trans-Retinoic acid, 9-cis-retinoic acid h (Zhu et al. 2002)
Cordyceps sinensis mycelium h (Huang et al. 2004)
Egonol gentiobioside, egonol gentiotrioside i (Lu D et al. 2012)
Epidermal growth factor h (Watanabe et al. 2006)
Flavonoids (quercetin, genistein at 10 μM) i (Sanderson JT et al. 2004)
Forskolin g (Watanabe et al. 2005)
Buthus martensi Karsch (BMK) extract i (Jin et al. 2006)
Zeranol g (Zhong et al. 2010)
Physiological compounds:
Ceramide h (Zhao et al. 1996)
Collagen h (Tan et al. 2015)
Cortisol platelet-derived growth factor BB h (Schmidt and Löffler 1997)
Epidermal growth factor i (Jin et al. 2006)
17β-Estradiol g (in men) (Dieudonné et al. 2006)
Interleukin 6 i (Lou et al. 2005)
Leptin g (in men) (Dieudonné et al. 2006; Pino et al. 2006);
Progesterone h (Purohit et al. 2005)
Prostaglandins (PG) A1, PGB2, PGD2, PGE1, PGE2 h (Heneweer et al. 2004; Watanabe et al. 2006; Chen D et al. 2007; Tan et al. 2015)
Protein kinase h (Watanabe et al. 2006)
Redox-regulated transcription factor, NRF2h (Muralimanoharan et al. 2018)
Retinoic acid receptor system RAR-RXR heterodimer ligands combined h (TTNPB and LG100268) (Mu, Yanase, Nishi, Hirase, et al. 2000)
Testosterone, 5α-dihydrotestosterone i (Stillman et al. 1991)
Transforming growth factor-β1 i (Stillman et al. 1991)
Tumor necrosis factor-α h (Zhao et al. 1996)
Physiological conditions and illnesses:
Bladder cancer (tumor related stroma) g (Nguyen et al. 2017; Wu et al. 2018)
Other compounds, including drug candidates:
2-Phenylbenzo[b]furans i (Pu et al. 2016)
Bisphenol A, lindane b (shorter time pre-incubation) (Nativelle-Serpentini et al. 2003)
Brominated flame retardants i (2,4,6-tribromophenol) (Cantón et al. 2005)
8-Bromo-cyclic adenosine monophosphate (Heneweer et al. 2004)
Ethanol i (Eng et al. 2002; Linardi et al. 2017)
Fungicides—benzimidazole i (benomyl, and metabolite, carbendazim) (Morinaga et al. 2004)
Fungicides h (vinclozolin, prochloraz) (Sanderson JT et al. 2002; Rieke et al. 2014)
Herbicides, triazines h (atrazine, simazine, propazine, and metabolites-atrazine-desethyl, atrazine-desisopropyl) (Sanderson JT et al. 2000; Sanderson JT et al. 2001)
2-Hydroxy-BDE-123, 2-MeO-BDE-123 i (Song et al. 2008)
Lactones (CRI-1, CRI-4 or Vioxx, CRI-11 and CRI-13) b (Sanderson T et al. 2008)
Lindane, bisphenol A i (shorter incubation time, up to 6 h) (Nativelle-Serpentini et al. 2003)
3-Methylcholanthrene g (weak inducer) (Ning et al. 2008)
1-Methyl-3-isobutylxanthine h (Sanderson JT et al. 2002)
Pesticides h (aldrin, chlordane, cypermethrin, parathion-methyl, endosulfan, methoxychlor, oxadiazon, metolachlor and atrazine after 24 h of exposure; tributyltin at 1 nM and 3 nM after 2 h and 24 h of exposure) (Laville et al. 2006)
Pesticides i (terbuthylazine, propiconazolem prothioconazole-weak inducers) and pesticide mixtures i (Kjeldsen et al. 2013)
Pesticides, herbicides h (atrazine, aldrin, chlordane, cypermethrin, parathion-methyl, endosulfan, methoxychlor, oxadiazon, metolachlor, terbuthylazine, propiconazole, prothioconazole, methomyl, pirimicarb, propamocarb, iprodion) (Andersen et al. 2002; Laville et al. 2006; Kjeldsen et al. 2013)
Phorbol 12-myristate 13-acetate i (Heneweer et al. 2004; Jin et al. 2006)
Polybrominated diphenyl ethers h (e.g. 2-hydroxy-BDE-123, 2-MeO-BDE-123 ) (Song et al. 2008)
Polychlorinated biphenyls h (PCB126, at high concentrations)(Li 2007)
2-Pyridinyl-substituted γ-naphthoflavones (at concentrations <1 μM) (Sanderson JT et al. 2004)
Ro40–6055 h (retinoic acid receptor α (RARα)-selective activator) (Zhu et al. 2002)
Steroidal derivatives (6-oxoandrostenedione)
2,4,6-Tribromophenol, BDE38 i (Cantón et al. 2005)

Footnotes

^aCompetitive inhibition, binding to enzyme active site

^bDecreased/suppressed/inhibited activity/product formation

^cReduced/suppressed mRNA and/or protein level/expression and activity

^dSuicide inactivator(s)

^eCompetitive inhibition, ligand binding

^fGene downregulated/suppressed

^gUp-regulation of biosynthesis, increased expression of protein

^hIncreased transcription/mRNA/protein expression/levels /and/or catalytic activity

ⁱIncreased activity, and/or increased product formation

^jAt cytotoxic concentrations