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. 1992 Nov;98:75–80. doi: 10.1289/ehp.929875

Elucidation of catalytic specificities of human cytochrome P450 and glutathione S-transferase enzymes and relevance to molecular epidemiology.

F P Guengerich 1, T Shimada 1, K D Raney 1, C H Yun 1, D J Meyer 1, B Ketterer 1, T M Harris 1, J D Groopman 1, F F Kadlubar 1
PMCID: PMC1519604  PMID: 1486866

Abstract

A number of different approaches have been used to determine the catalytic selectivity of individual human enzymes toward procarcinogens. Studies with cytochrome P450 (P450) enzymes and glutathione S-transferases are summarized here, and recent work with pyrrolizidine alkaloids, aflatoxins, 4,4'-methylenebis(2-chloroaniline), and ethyl carbamate is discussed. In some cases a single enzyme can catalyze both activation and detoxication reactions of a chemical. The purification and characterization of human lung P4501A1 and the development of a noninvasive assay for human P4502E1 are also described.

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Selected References

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  1. Aoyama T., Yamano S., Guzelian P. S., Gelboin H. V., Gonzalez F. J. Five of 12 forms of vaccinia virus-expressed human hepatic cytochrome P450 metabolically activate aflatoxin B1. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4790–4793. doi: 10.1073/pnas.87.12.4790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Butler M. A., Guengerich F. P., Kadlubar F. F. Metabolic oxidation of the carcinogens 4-aminobiphenyl and 4,4'-methylene-bis(2-chloroaniline) by human hepatic microsomes and by purified rat hepatic cytochrome P-450 monooxygenases. Cancer Res. 1989 Jan 1;49(1):25–31. [PubMed] [Google Scholar]
  3. Butler M. A., Iwasaki M., Guengerich F. P., Kadlubar F. F. Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7696–7700. doi: 10.1073/pnas.86.20.7696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Forrester L. M., Neal G. E., Judah D. J., Glancey M. J., Wolf C. R. Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8306–8310. doi: 10.1073/pnas.87.21.8306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Guengerich F. P., Kim D. H. Enzymatic oxidation of ethyl carbamate to vinyl carbamate and its role as an intermediate in the formation of 1,N6-ethenoadenosine. Chem Res Toxicol. 1991 Jul-Aug;4(4):413–421. doi: 10.1021/tx00022a003. [DOI] [PubMed] [Google Scholar]
  6. Guengerich F. P., Kim D. H., Iwasaki M. Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol. 1991 Mar-Apr;4(2):168–179. doi: 10.1021/tx00020a008. [DOI] [PubMed] [Google Scholar]
  7. Guengerich F. P., Liebler D. C. Enzymatic activation of chemicals to toxic metabolites. Crit Rev Toxicol. 1985;14(3):259–307. doi: 10.3109/10408448509037460. [DOI] [PubMed] [Google Scholar]
  8. Guengerich F. P., Martin M. V., Beaune P. H., Kremers P., Wolff T., Waxman D. J. Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem. 1986 Apr 15;261(11):5051–5060. [PubMed] [Google Scholar]
  9. Guengerich F. P. Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol. 1990 Jul-Aug;3(4):363–371. doi: 10.1021/tx00016a015. [DOI] [PubMed] [Google Scholar]
  10. Guengerich F. P. Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol. 1988 May;33(5):500–508. [PubMed] [Google Scholar]
  11. Guengerich F. P., Shimada T. Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem Res Toxicol. 1991 Jul-Aug;4(4):391–407. doi: 10.1021/tx00022a001. [DOI] [PubMed] [Google Scholar]
  12. Guengerich F. P., Turvy C. G. Comparison of levels of several human microsomal cytochrome P-450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. J Pharmacol Exp Ther. 1991 Mar;256(3):1189–1194. [PubMed] [Google Scholar]
  13. Holeski C. J., Eaton D. L., Monroe D. H., Bellamy G. M. Effects of phenobarbital on the biliary excretion of aflatoxin P1-glucuronide and aflatoxin B1-S-glutathione in the rat. Xenobiotica. 1987 Feb;17(2):139–153. doi: 10.3109/00498258709043924. [DOI] [PubMed] [Google Scholar]
  14. Kensler T. W., Egner P. A., Dolan P. M., Groopman J. D., Roebuck B. D. Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones. Cancer Res. 1987 Aug 15;47(16):4271–4277. [PubMed] [Google Scholar]
  15. Kitada M., Taneda M., Ohta K., Nagashima K., Itahashi K., Kamataki T. Metabolic activation of aflatoxin B1 and 2-amino-3-methylimidazo[4,5-f]-quinoline by human adult and fetal livers. Cancer Res. 1990 May 1;50(9):2641–2645. [PubMed] [Google Scholar]
  16. MacLeod M. C., Zachary K. L. Involvement of the exocyclic amino group of deoxyguanosine in DNA-catalysed carcinogen detoxification. Carcinogenesis. 1985 Jan;6(1):147–149. doi: 10.1093/carcin/6.1.147. [DOI] [PubMed] [Google Scholar]
  17. Miller E. C., Miller J. A. Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer. 1981 May 15;47(10):2327–2345. doi: 10.1002/1097-0142(19810515)47:10<2327::aid-cncr2820471003>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  18. Miranda C. L., Reed R. L., Guengerich F. P., Buhler D. R. Role of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver. Carcinogenesis. 1991 Mar;12(3):515–519. doi: 10.1093/carcin/12.3.515. [DOI] [PubMed] [Google Scholar]
  19. Perrot N., Nalpas B., Yang C. S., Beaune P. H. Modulation of cytochrome P450 isozymes in human liver, by ethanol and drug intake. Eur J Clin Invest. 1989 Dec;19(6):549–555. doi: 10.1111/j.1365-2362.1989.tb00273.x. [DOI] [PubMed] [Google Scholar]
  20. Peter R., Böcker R., Beaune P. H., Iwasaki M., Guengerich F. P., Yang C. S. Hydroxylation of chlorzoxazone as a specific probe for human liver cytochrome P-450IIE1. Chem Res Toxicol. 1990 Nov-Dec;3(6):566–573. doi: 10.1021/tx00018a012. [DOI] [PubMed] [Google Scholar]
  21. Shimada T., Guengerich F. P. Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver. Proc Natl Acad Sci U S A. 1989 Jan;86(2):462–465. doi: 10.1073/pnas.86.2.462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shimada T., Iwasaki M., Martin M. V., Guengerich F. P. Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA 1535/pSK1002. Cancer Res. 1989 Jun 15;49(12):3218–3228. [PubMed] [Google Scholar]
  23. Williams D. E., Reed R. L., Kedzierski B., Dannan G. A., Guengerich F. P., Buhler D. R. Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver. Drug Metab Dispos. 1989 Jul-Aug;17(4):387–392. [PubMed] [Google Scholar]
  24. Yun C. H., Shimada T., Guengerich F. P. Purification and characterization of human liver microsomal cytochrome P-450 2A6. Mol Pharmacol. 1991 Nov;40(5):679–685. [PubMed] [Google Scholar]

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