The Role of Cytochrome P450 Enzymes in Endogenous Signalling Pathways and Environmental Carcinogenesis

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2006 Nov 28

PMID 17128211

Citations 327

Authors

Daniel W Nebert

Timothy P Dalton

Affiliations

Soon will be listed here.

Abstract

Some cytochrome P450 (CYP) heme-thiolate enzymes participate in the detoxication and, paradoxically, the formation of reactive intermediates of thousands of chemicals that can damage DNA, as well as lipids and proteins. CYP expression can also affect the production of molecules derived from arachidonic acid, and alters various downstream signal-transduction pathways. Such changes can be precursors to malignancy. Recent studies in mice have changed our perceptions about the function of CYP1 enzymes. We suggest a two-tiered system to predict an overall inter-individual risk of tumorigenesis based on DNA variants in certain 'early defence' CYP genes, combined with polymorphisms in various downstream target genes.

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References

Nemeti B, Gregus Z . Glutathione-dependent reduction of arsenate in human erythrocytes--a process independent of purine nucleoside phosphorylase. Toxicol Sci. 2004; 82(2):419-28. DOI: 10.1093/toxsci/kfh301. View

WATTENBERG L . Effects of dietary constituents on the metabolism of chemical carcinogens. Cancer Res. 1975; 35(11 Pt. 2):3326-31. View

Rodriguez-Antona C, Ingelman-Sundberg M . Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006; 25(11):1679-91. DOI: 10.1038/sj.onc.1209377. View

Cribb A, Knight M, Dryer D, Guernsey J, Hender K, Tesch M . Role of polymorphic human cytochrome P450 enzymes in estrone oxidation. Cancer Epidemiol Biomarkers Prev. 2006; 15(3):551-8. DOI: 10.1158/1055-9965.EPI-05-0801. View

Ingelman-Sundberg M . Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci. 2004; 25(4):193-200. DOI: 10.1016/j.tips.2004.02.007. View

Porter R, Jachymova M, Martasek P, Kalyanaraman B, Vasquez-Vivar J . Reductive activation of Cr(Vi) by nitric oxide synthase. Chem Res Toxicol. 2005; 18(5):834-43. DOI: 10.1021/tx049778e. View

Qatanani M, Moore D . CAR, the continuously advancing receptor, in drug metabolism and disease. Curr Drug Metab. 2005; 6(4):329-39. DOI: 10.2174/1389200054633899. View

Nebert D, McKinnon R . Cytochrome P450: evolution and functional diversity. Prog Liver Dis. 1994; 12:63-97. View

Cooper A . Hepatic uptake of chylomicron remnants. J Lipid Res. 1997; 38(11):2173-92. View

10.

Harstad E, Guite C, Thomae T, Bradfield C . Liver deformation in Ahr-null mice: evidence for aberrant hepatic perfusion in early development. Mol Pharmacol. 2006; 69(5):1534-41. DOI: 10.1124/mol.105.020107. View

11.

Plastaras J, Guengerich F, Nebert D, Marnett L . Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde. J Biol Chem. 2000; 275(16):11784-90. DOI: 10.1074/jbc.275.16.11784. View

12.

Nemeti B, Csanaky I, Gregus Z . Effect of an inactivator of glyceraldehyde-3-phosphate dehydrogenase, a fortuitous arsenate reductase, on disposition of arsenate in rats. Toxicol Sci. 2005; 90(1):49-60. DOI: 10.1093/toxsci/kfj058. View

13.

Mossman B, Lounsbury K, Reddy S . Oxidants and signaling by mitogen-activated protein kinases in lung epithelium. Am J Respir Cell Mol Biol. 2006; 34(6):666-9. PMC: 2644227. DOI: 10.1165/rcmb.2006-0047SF. View

14.

Williams R . The metabolism of certain drugs and food chemicals in man. Ann N Y Acad Sci. 1971; 179:141-54. DOI: 10.1111/j.1749-6632.1971.tb46896.x. View

15.

Nestel P, HAVEL R, Bezman A . SITES OF INITIAL REMOVAL OF CHYLOMICRON TRIGLYCERIDE FATTY ACIDS FROM THE BLOOD. J Clin Invest. 1962; 41(10):1915-21. PMC: 291116. DOI: 10.1172/JCI104648. View

16.

Wolf C, Smith C, Bishop T, Forman D, Gough A, Spurr N . CYP2D6 genotyping and the association with lung cancer susceptibility. Pharmacogenetics. 1994; 4(2):104-6. DOI: 10.1097/00008571-199404000-00008. View

17.

Crabb D, Matsumoto M, Chang D, You M . Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology. Proc Nutr Soc. 2004; 63(1):49-63. DOI: 10.1079/pns2003327. View

18.

Ma X, Idle J, Malfatti M, Krausz K, Nebert D, Chen C . Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis. 2006; 28(3):732-7. PMC: 1829392. DOI: 10.1093/carcin/bgl184. View

19.

Buters J, Sakai S, Richter T, Pineau T, Alexander D, Savas U . Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. Proc Natl Acad Sci U S A. 1999; 96(5):1977-82. PMC: 26722. DOI: 10.1073/pnas.96.5.1977. View

20.

Hishida A, Terakura S, Emi N, Yamamoto K, Murata M, Nishio K . GSTT1 and GSTM1 deletions, NQO1 C609T polymorphism and risk of chronic myelogenous leukemia in Japanese. Asian Pac J Cancer Prev. 2005; 6(3):251-5. View