Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis

Key Points

  • The metabolism of xenobiotics by xenobiotic-metabolizing enzymes (XMEs) has been classified into phase I (functionalization) and phase II (conjugation) reactions. Cytochrome P450 (CYP) enzymes comprise 70–80% of all phase I XMEs.

  • Although originally thought to be responsible for drug metabolism almost exclusively in the liver, it has now been realized that all XMEs participate in many crucial endogenous functions, probably in every eukaryotic cell and many prokaryotes.

  • Of the 57 human CYP genes in 18 families, the members of the CYP1 to CYP4 families oxygenate thousands of xenobiotics (and endogenous substrates), whereas all members of the CYP5 family and higher principally metabolize endogenous substrates in a highly substrate-specific manner.

  • CYP enzymes can cause tumour initiation through the formation of reactive intermediates (from exogenous and endogenous substrates). CYPs also participate in tumour initiation and progression through inflammation, other eicosanoid-mediated processes and other signal-transduction pathways.

  • There is an interesting 'xenosensor' relationship that is not yet well understood among CYPs, XME receptors that regulate CYP expression and xenobiotic-related transporters (XRTs).

  • Although several high-penetrance, predominantly monogenic (hPpM), traits including cancer have been correlated with various human CYP genes, the identification of a specific procarcinogen is rarely possible.

  • Pharmacokinetic studies of several environmental toxicants in Cyp1 knockout mouse lines have shown that CYP1A1, CYP1A2 and CYP1B1 might be beneficial or detrimental — depending on their time-specific, organ-specific, tissue-specific and cell-type-specific expression. These new findings suggest that animal studies and human epidemiological studies might need to be revisited.

  • Whereas oral drugs more commonly use the portal vein system (and first-pass elimination kinetics), we suggest that the lymphatic system might be more important in delivering the very hydrophobic oral polycyclic aromatic hydrocarbons (PAHs) and polyhalogenated aromatic hydrocarbons (PHAHs) to target tissues. This is especially relevant to clinical medicine, because oral exposure to these procarcinogens is the most predominant route. More focus on pharmacokinetic and pharmacodynamic studies of hydrophobic procarcinogens in animal models (and extrapolation to humans) is needed.

  • A two-tiered model is proposed for the risk of developing cancer as a result of the environment. First, human inter-individual differences in the up-front hPpM traits, encoded by phase I genes, should have profound effects on a small (5–15%) proportion of any population who have no significant polymorphisms in downstream target genes. Second, all downstream targets of phase-I-mediated reactive intermediates can have their own important polymorphisms, always resulting in a unimodal gradient response.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Classical schemes.
Figure 2: The distribution of CYP2D6 metabolic ratio values in cigarette smokers with and without lung cancer.
Figure 3: CYP1–AHR 'regulatory-loop' paradigm.

Similar content being viewed by others

References

  1. Nebert, D. W. & Russell, D. W. Clinical importance of the cytochromes P450. Lancet 360, 1155–1162 (2002). One of only a handful of CYP reviews that emphasizes the clinical relevance of CYP enzymes, instead of CYP metabolism of drugs or environmental procarcinogens.

    Article  CAS  PubMed  Google Scholar 

  2. Nelson, D. R. et al. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14, 1–18 (2004). A comparison of all CYP genes in the human genome with all CYP genes in the mouse genome by BLAST searches with each and every CYP exon, resulting in the discovery of many pseudogenes, partial pseudogenes and detritus exons.

    Article  CAS  PubMed  Google Scholar 

  3. Nelson, D. R. et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6, 1–42 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Valko, M., Rhodes, C. J., Moncol, J., Izakovic, M. & Mazur, M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact. 160, 1–40 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Fortini, P. et al. 8-Oxoguanine DNA damage: at the crossroad of alternative repair pathways. Mutat. Res. 531, 127–139 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Undevia, S. D., Gomez-Abuin, G. & Ratain, M. J. Pharmacokinetic variability of anticancer agents. Nature Rev. Cancer 5, 447–458 (2005).

    Article  CAS  Google Scholar 

  7. Williams, R. T. Detoxication Mechanisms: The Metabolism of Drugs and Allied Organic Compounds (Chapman and Hall, London, 1949).

    Google Scholar 

  8. Evans, W. E. & Relling, M. V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Williams, R. T. The metabolism of certain drugs and food chemicals in man. Ann. N. Y. Acad. Sci. 179, 141–154 (1971). The classical field of drug metabolism is reviewed for the last time by one of the most famous scientists in that field, Richard Tecwyn Williams. He died in 1979 at the age of 70.

    Article  CAS  PubMed  Google Scholar 

  10. Nebert, D. W., Jorge-Nebert, L. & Vesell, E. S. Pharmacogenomics and 'individualized drug therapy': high expectations and disappointing achievements. Am. J. Pharmacogenomics 3, 361–370 (2003).

    Article  PubMed  Google Scholar 

  11. Ambrosone, C. B. et al. Cigarette smoking, N-acetyltransferase-2 genetic polymorphisms, and breast cancer risk. JAMA 276, 1494–1501 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Hishida, A. et al. GSTT1 and GSTM1 deletions, NQO1 C609T polymorphism and risk of chronic myelogenous leukemia in Japanese. Asian Pac. J. Cancer Prev. 6, 251–255 (2005).

    PubMed  Google Scholar 

  13. Landi, S. et al. A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of colorectal cancer. Pharmacogenet. Genomics 15, 535–546 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Nebert, D. W. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am. J. Hum. Genet. 60, 265–271 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Omura, T. & Sato, R. A new cytochrome in liver microsomes. J. Biol. Chem. 237, 1375–1376 (1962).

    Article  CAS  PubMed  Google Scholar 

  16. Bachschmid, M., Schildknecht, S. & Ullrich, V. Redox regulation of vascular prostanoid synthesis by the nitric oxide-superoxide system. Biochem. Biophys. Res. Commun. 338, 536–542 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Nebert, D. W. et al. The P450 gene superfamily: recommended nomenclature. DNA 6, 1–11 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Nebert, D. W. Proposed role of drug-metabolizing enzymes: regulation of steady state levels of the ligands that effect growth, homeostasis, differen-tiation, and neuroendocrine functions. Mol. Endocrinol. 5, 1203–1214 (1991). The review that first predicted the regulatory loops and interactive exogenous and endogenous signalling pathways involving the up-regulation of XMEs by their XME receptors.

    Article  CAS  PubMed  Google Scholar 

  19. Nebert, D. W. & Dieter, M. Z. The evolution of drug metabolism. Pharmacology 61, 124–135 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Ingelman-Sundberg, M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol. Sci. 25, 193–200 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Nebert, D. W. & Vesell, E. S. Advances in pharmacogenomics and individualized drug therapy: exciting challenges that lie ahead. Eur. J. Pharmacol. 500, 267–280 (2004). Contrary to more than 1,000 reviews that predict that 'pharmacogenomics will be successful in individualizing drug therapy very soon', this review points out the many difficulties with trying to determine an unequivocal phenotype or genotype.

    Article  CAS  PubMed  Google Scholar 

  22. Johansson, I. et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultra-rapid metabolism of debrisoquine. Proc. Natl Acad. Sci. USA 90, 11825–11829 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wattenberg, L. W. Effects of dietary constituents on the metabolism of chemical carcinogens. Cancer Res. 35, 3326–3331 (1975).

    CAS  PubMed  Google Scholar 

  24. Conney, A. H. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res. 42, 4875–4917 (1982). This review summarizes the cutting-edge research of 'enzyme induction' by Allan H. Conney and colleagues that spans the previous three decades.

    CAS  PubMed  Google Scholar 

  25. Cerutti, P. A. Prooxidant states and tumor promotion. Science 227, 375–381 (1985).

    Article  CAS  PubMed  Google Scholar 

  26. Guengerich, F. P. Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy. Cancer Res. 48, 2946–2954 (1988). Describes the research of the Guengerich laboratory and other laboratories in elucidating the relationship between CYP enzyme activities and both tumorigenesis and cancer chemotherapy – spanning the previous two decades.

    CAS  PubMed  Google Scholar 

  27. Nebert, D. W. The Ah locus: genetic differences in toxicity, cancer, mutation, and birth defects. Crit. Rev. Toxicol. 20, 153–174 (1989).

    Article  CAS  PubMed  Google Scholar 

  28. Kouri, R. E. et al. Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cryopreserved lymphocytes. Cancer Res. 42, 5030–5037 (1982).

    CAS  PubMed  Google Scholar 

  29. Kouri, R. E., McLemore, T., Jaiswal, A. K. & Nebert, D. W. Current cellular assays for measuring clinical drug metabolizing capacity––impact of new molecular biologic techniques. Progr. Clin. Biol. Res. 214, 453–469 (1986).

    CAS  Google Scholar 

  30. Idle, J. R. et al. Some observations on the oxidation phenotype status of Nigerian patients presenting with cancer. Cancer Lett. 11, 331–338 (1981).

    Article  CAS  PubMed  Google Scholar 

  31. Ayesh, R., Idle, J. R., Ritchie, J. C., Crothers, M. J. & Hetzel, M. R. Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature 312, 169–170 (1984).

    Article  CAS  PubMed  Google Scholar 

  32. Mahgoub, A., Idle, J. R., Dring, L. G., Lancaster, R. & Smith, R. L. Polymorphic hydroxylation of debrisoquine in man. Lancet 2, 584–586 (1977).

    Article  CAS  PubMed  Google Scholar 

  33. Caporaso, N. et al. Lung cancer risk, occupational exposure, and the debrisoquine metabolic phenotype. Cancer Res. 49, 3675–3679 (1989).

    CAS  PubMed  Google Scholar 

  34. Mossman, B. T., Lounsbury, K. M. & Reddy, S. P. Oxidants and signaling by mitogen-activated protein kinases in lung epithelium. Am. J. Respir. Cell Mol. Biol. 34, 666–669 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wolf, C. R. et al. CYP2D6 genotyping and the association with lung cancer susceptibility. Pharmacogenetics 4, 104–106 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. London, S. J., Daly, A. K., Thomas, D. C., Caporaso, N. E. & Idle, J. R. Methodological issues in the interpretation of studies of the CYP2D6 genotype in relation to lung cancer risk. Pharmacogenetics 4, 107–108 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Nebert, D. W., Dalton, T. P., Okey, A. B. & Gonzalez, F. J. Role of aryl hydrocarbon receptor-mediated induc-tion of the CYP1 enzymes in environmental toxicity and cancer. J. Biol. Chem. 279, 23847–23850 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Currier, N. et al. Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicol. Pathol. 33, 726–737 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Ohtake, F. et al. Modulation of oestrogen receptor signaling by association with the activated dioxin receptor. Nature 423, 545–550 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Puga, A. et al. Aromatic hydrocarbon receptor interaction with the retinoblastoma protein poten-tiates repression of E2F-dependent transcription and cell cycle arrest. J. Biol. Chem. 275, 2943–2950 (2000). The most recent paper to review the many functions of the aryl hydrocarbon receptor; not only does the AHR regulate drug-metabolizing and xenobiotic-metabolizing enzymes, but the AHR participates in many signal transduction pathways associated with embryonic and fetal development, central nervous system development and the cell cycle.

    Article  CAS  PubMed  Google Scholar 

  41. Park, K. T., Mitchell, K. A., Huang, G. & Elferink, C. J. The aryl hydrocarbon receptor predisposes hepato-cytes to Fas-mediated apoptosis. Mol. Pharmacol. 67, 612–622 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Nebert, D. W. et al. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem. Pharmacol. 59, 65–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Cribb, A. E. et al. Role of polymorphic human cytochrome P450 enzymes in estrone oxidation. Cancer Epidemiol. Biomarkers Prev. 15, 551–558 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Sarfarazi, M. & Stoilov, I. Molecular genetics of primary congenital glaucoma. Eye 14 (Pt 3B), 422–428 (2000).

    Article  PubMed  Google Scholar 

  45. Jiang, Z. et al. Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype. Pharmacogenet. Genomics 16, 359–367 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Capdevila, J. H., Harris, R. C. & Falck, J. R. Microsomal cytochrome P450 and eicosanoid metabolism. Cell Mol. Life Sci. 59, 780–789 (2002). Latest review by Jorge Capdevila, who has championed the field showing that many (if not all) CYP enzymes in the CYP1, CYP2, CYP3 and CYP4 gene families participate in both the synthesis and degradation of innumerable eicosanoids.

    Article  CAS  PubMed  Google Scholar 

  47. Nebert, D. W. Drug-metabolizing enzymes in ligand-modulated transcription. Biochem. Pharmacol. 47, 25–37 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Diaz-Cruz, E. S. & Brueggemeier, R. W. Interrelationships between cyclooxygenases and aromatase: unraveling the relevance of cyclooxygenase inhibitors in breast cancer. Anticancer Agents Med. Chem. 6, 221–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Telliez, A., Furman, C., Pommery, N. & Henichart, J. P. Mechanisms leading to COX2 expression and COX2-induced tumorigenesis: topical therapeutic strategies targeting COX2 expression and activity. Anticancer Agents Med. Chem. 6, 187–208 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Murakami, M. & Kudo, I. Prostaglandin E synthase: a novel drug target for inflammation and cancer. Curr. Pharm. Des 12, 943–954 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Nebert, D. W. in Toward a Molecular Basis of Alcohol Use and Abuse (eds Jansson, B., Jörnvall, H., Rydberg, U., Terenius, L. & Vallee, B.) 231–240 (Nobel Symposium Press, Stockholm, 1994).

    Book  Google Scholar 

  53. Li, A. G., Lu, S. L., Han, G., Hoot, K. E. & Wang, X. J. Role of TGFβ in skin inflammation and carcinogenesis. Mol. Carcinog. 45, 389–396 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Clevers, H. At the crossroads of inflammation and cancer. Cell 118, 671–674 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Mannering, G. J., Shoeman, J. A. & Deloria, L. B. Identification of the antibiotic hops component, colupulone, as an inducer of hepatic cytochrome P-4503A in the mouse. Drug Metab. Dispos. 20, 142–147 (1992).

    CAS  PubMed  Google Scholar 

  56. Qatanani, M. & Moore, D. D. CAR, the continuously advancing receptor, in drug metabolism and disease. Curr. Drug Metab. 6, 329–339 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Kalaany, N. Y. & Mangelsdorf, D. J. LXRs and FXR: the yin and yang of cholesterol and fat metabolism. Annu. Rev. Physiol. 68, 159–191 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Zelcer, N. & Tontonoz, P. Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Invest. 116, 607–614 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nebert, D. W. & McKinnon, R. A. Cytochrome P450: evolution and functional diversity. Prog. Liver Dis. 12, 63–97 (1994).

    CAS  PubMed  Google Scholar 

  60. Clowes, J. A., Riggs, B. L. & Khosla, S. The role of the immune system in the pathophysiology of osteoporosis. Immunol. Rev. 208, 207–227 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Chawla, A., Repa, J. J., Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Kakizaki, S., Karami, S. & Negishi, M. Retinoic acids repress constitutive active receptor-mediated induction by 1, 4-bis[2-(3, 5-dichloropyridyloxy)]benzene of the Cyp2b10 gene in mouse primary hepatocytes. Drug Metab. Dispos. 30, 208–211 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Bikle, D. D., Xie, Z., Ng, D., Tu, C. L. & Oda, Y. Squamous cell carcinomas fail to respond to the prodifferentiating actions of 1, 25-(OH)2-vitamin D: why? Recent Results Cancer Res. 164, 111–122 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Chen, G. & White, P. A. The mutagenic hazards of aquatic sediments: a review. Mutat. Res. 567, 151–225 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Jansen, M. S. et al. Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc. Natl Acad. Sci. USA 101, 7199–7204 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Geier, A. et al. Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis. Hepatology 38, 345–354 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Grover, P. L. & Sims, P. Enzyme-catalysed reactions of polycyclic hydrocarbons with deoxyribonucleic acid and protein in vitro. Biochem. J. 110, 159–160 (1968). This 2-page publication was 'the shot heard 'round the world'. Their findings completely changed the thinking of most colleagues in the field for the next three decades.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dalton, T. P. et al. Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery. Biochem. Biophys. Res. Commun. 267, 184–189 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Liang, H. C. et al. Cyp1a2(−/−) null mutant mice develop normally but show deficient drug metabolism. Proc. Natl Acad. Sci. USA 93, 1671–1676 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Buters, J. T. et al. Cytochrome P450 CYP1B1 deter-mines susceptibility to 7, 12-dimethylbenz[a]anth-racene-induced lymphomas. Proc. Natl Acad. Sci. USA 96, 1977–1982 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Harstad, E. B., Guite, C. A., Thomae, T. L. & Bradfield, C. A. Liver deformation in Ahr-null mice: evidence for aberrant hepatic perfusion in early development. Mol. Pharmacol. 69, 1534–1541 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Fernandez-Salguero, P. et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268, 722–726 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Uno, S. et al. Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. Mol. Pharmacol. 65, 1225–1237 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Uno, S. et al. Oral benzo[a]pyrene in Cyp1 knockout mouse lines: CYP1A1 important in detoxication, CYP1B1 metabolism required for immune damage independent of total-body burden and clearance rate. Mol. Pharmacol. 69, 1103–1114 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Tsuneoka, Y. et al. 4-Aminobiphenyl-induced liver and urinary bladder DNA adduct formation in Cyp1a2(−/−) and Cyp1a2(+/+) mice. J. Natl Cancer Inst. 95, 1227–1237 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Ma, X. et al. Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP). Carcinogenesis 25 Oct 2006 [epub ahead of print].

    Google Scholar 

  77. Mohr, U., Emura, M., Aufderheide, M., Riebe, M. & Ernst, H. Possible role of genetic predisposition in multi-generation carcinogenesis. IARC Sci. Publ. 96, 93–103 (1989).

    Google Scholar 

  78. Dragin, N., Dalton, T. P., Miller, M. L., Shertzer, H. G. & Nebert, D. W. For dioxin-induced birth defects, mouse or human CYP1A2 in maternal liver protects whereas mouse CYP1A1 and CYP1B1 are inconsequential. J. Biol. Chem. 281, 18591–18600 (2006). Shows that maternal (mouse or human) hepatic CYP1A2 acts like a 'sink' to sequester dioxin (and presumably other extremely hydrophobic coplanar environmental toxicants), resulting in a substantial decrease in the amount of said environmental toxicant reaching the developing baby in utero.

    Article  CAS  PubMed  Google Scholar 

  79. Eaton, D. L., Gallagher, E. P., Bammler, T. K. & Kunze, K. L. Role of cytochrome P450 1A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity. Pharmacogenetics 5, 259–274 (1995).

    Article  CAS  PubMed  Google Scholar 

  80. Nebert, D. W., McKinnon, R. A. & Puga, A. Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol. 15, 273–280 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Feng, B. Y. & Shoichet, B. K. Synergy and antagonism of promiscuous inhibition in multiple-compound mixtures. J. Med. Chem. 49, 2151–2154 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Okey, A. B., Boutros, P. C. & Harper, P. A. Polymorphisms of human nuclear receptors that control expression of drug-metabolizing enzymes. Pharmacogenet. Genomics 15, 371–379 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Cybulski, C. et al. CHEK2 is a multi-organ cancer susceptibility gene. Am. J. Hum. Genet. 75, 1131–1135 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Stacey, S. N. et al. The BARD1 Cys557Ser variant and breast cancer risk in Iceland. PLoS Med. 3, e217 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Nelson, D. R. Cytochrome P450 and the individuality of species. Arch. Biochem. Biophys. 369, 1–10 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Routledge, P. A. & Shand, D. G. Presystemic drug elimination. Annu. Rev. Pharmacol. Toxicol. 19, 447–468 (1979). Describes for the first time the concept and mech-anism of 'first-pass elimination kinetics', involving drug absorption from the gastro-intestinal tract, which can follow the oral administration of drugs.

    Article  CAS  PubMed  Google Scholar 

  87. Nestel, P. J., Havel, R. J. & Bezman, A. Sites of initial removal of chylomicron triglyceride fatty acids from the blood. J. Clin. Invest. 41, 1915–1921 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Nestel, P. J., Havel, R. J. & Bezman, A. Metabolism of constituent lipids of dog chylomicrons. J. Clin. Invest. 42, 1313–1321 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Stary, H. C. Macrophages, macrophage foam cells, and eccentric intimal thickening in the coronary arteries of young children. Atherosclerosis 64, 91–108 (1987).

    Article  CAS  PubMed  Google Scholar 

  90. Norum, K. R. & Blomhoff, R. McCollum Award Lecture, 1992: vitamin A absorption, transport, cellular uptake, and storage. Am. J. Clin. Nutr. 56, 735–744 (1992).

    Article  CAS  PubMed  Google Scholar 

  91. Cooper, A. D. Hepatic uptake of chylomicron remnants. J. Lipid Res. 38, 2173–2192 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Yu, A. M., et al. Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6. Pharmacogenetics 13, 173–181 (2003). Describes how the insertion of a BAC clone into the mouse genome, to make a humanized CYP2D6 mouse line still carrying all nine of its functional Cyp2d mouse genes, was successful in showing that the human CYP2D6 enzyme participates in serotonin biosynthesis.

    Article  CAS  PubMed  Google Scholar 

  93. Jiang, Z. et al. Toward the evaluation of function in genetic variability: characterizing human SNP frequencies and establishing BAC-transgenic mice carrying the human CYP1A1_CYP1A2 locus. Hum. Mutat. 25, 196–206 (2005). Among the first publications to detect all double-hit and single-hit SNPs across the 39.6 kb of the human CYP1A1–CYP1A2 locus, delineation of SNPs, and SNP allelic frequencies in African, East Asian and Caucasian populations. Also describes the generation of a humanized CYP1A1–CYP1A2 mouse line.

    Article  PubMed  Google Scholar 

  94. Cheung, C. et al. Differential metabolism of 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) in mice humanized for CYP1A1 and CYP1A2. Chem. Res. Toxicol. 18, 1471–1478 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Derkenne, S. et al. Theophylline pharmacokinetics: comparison of Cyp1a1(−/−) and Cyp1a2(−/−) knockout mice, humanized hCYP1A1_1A2 knock-in mice lacking either the mouse Cyp1a1 or Cyp1a2 gene, and Cyp1(+/+) wild-type mice. Pharmacogenet. Genomics 15, 503–511 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Moriguchi, T. et al. Distinct response to dioxin in an aryl hydrocarbon receptor (AHR)-humanized mouse. Proc. Natl Acad. Sci. USA 100, 5652–5657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Court DL, Sawitzke, J. A. & Thomason, L. C. Genetic engineering using homologous recombination. Annu. Rev. Genet. 36, 361–388 (2002)

    Article  CAS  PubMed  Google Scholar 

  98. Conney, A. H., Chang, R. L., Jerina, D. M. & Wei, S. J. Studies on the metabolism of benzo[a]pyrene and dose-dependent differences in the mutagenic profile of its ultimate carcinogenic metabolite. Drug Metab. Rev. 26, 125–163 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. DeCaprio, A. P. The toxicology of hydroquinone — relevance to occupational and environmental exposure. Crit. Rev. Toxicol. 29, 283–330 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Nemoto, N., Hirakawa, T. & Takayama, S. Effect of UDP glucuronic acid on the microsome-mediated binding of benzo[a]pyrene metabolites to calf thymus DNA. Carcinogenesis 1, 115–127 (1980).

    Article  CAS  PubMed  Google Scholar 

  101. Wollemann, M. & Feuer, G. Formation of fluoroacetyl-coenzyme A and fluoroacetylcholine from fluoroacetic acid and fluorocitric acid in brain extracts. Acta Physiol. Hung. 11, 165–172 (1957).

    CAS  PubMed  Google Scholar 

  102. Monks, T. J. et al. Glutathione conjugate-mediated toxicities. Toxicol. Appl. Pharmacol. 106, 1–19 (1990).

    Article  CAS  PubMed  Google Scholar 

  103. Gunaratnam, M. & Grant, M. H. The role of glutathione reductase in the cytotoxicity of chromium (VI) in isolated rat hepatocytes. Chem. Biol. Interact. 134, 191–202 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Pourahmad, J. & O'Brien, P. J. Biological reactive intermediates that mediate chromium (VI) toxicity. Adv. Exp. Med. Biol. 500, 203–207 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Gunaratnam, M., Pohlscheidt, M. & Grant, M. H. Pretreatment of rats with the inducing agents phenobarbitone and 3-methylcholanthrene ameliorates the toxicity of chromium (VI) in hepatocytes. Toxicol. In Vitro 16, 509–516 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Porter, R., Jachymova, M., Martasek, P., Kalyanaraman, B. & Vasquez-Vivar, J. Reductive activation of Cr(Vi) by nitric oxide synthase. Chem. Res. Toxicol. 18, 834–843 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Nemeti, B. & Gregus, Z. Glutathione-dependent reduction of arsenate in human erythrocytes — a process independent of purine nucleoside phosphorylase. Toxicol. Sci. 82, 419–428 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Nemeti, B. & Gregus, Z. Reduction of arsenate to arsenite by human erythrocyte lysate and rat liver cytosol: characterization of a glutathione- and NAD-dependent arsenate reduction linked to glycolysis. Toxicol. Sci. 85, 847–858 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. 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. 90, 49–60 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Mukherjee, B. et al. Glutathione S-transferase ω-1 and ω-2 pharmacogenomics. Drug Metab. Dispos. 34, 1237–1246 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Ramakrishna, G. & Anderson, L. M. Levels and membrane localization of the c-K-ras p21 protein in lungs of mice of different genetic strains and effects of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and Aroclor 1254. Carcinogenesis 19, 463–470 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Goth, L., Rass, P. & Pay, A. Catalase enzyme mutations and their association with diseases. Mol. Diagn. 8, 141–149 (2004).

    Article  PubMed  Google Scholar 

  113. Cocco, P. Does G6PD deficiency protect against cancer? A critical review. J. Epidemiol. Community Health 41, 89–93 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hein, D. W. N-acetyltransferase-2 genetic poly-morphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene 25, 1649–1658 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Terry, P. D. & Goodman, M. Is the association between cigarette smoking and breast cancer modified by genotype? A review of epidemiologic studies and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 15, 602–611 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Agundez, J. A. Cytochrome P450 gene polymorphism and cancer. Curr. Drug Metab. 5, 211–224 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Rodriguez-Antona, C. & Ingelman-Sundberg, M. Cytochrome P450 pharmacogenetics and cancer. Oncogene 25, 1679–1691 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Costa, L. G., Vitalone, A., Cole, T. B. & Furlong, C. E. Modulation of paraoxonase (PON1) activity. Biochem. Pharmacol. 69, 541–550 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Schroeder, J. C. Metabolic susceptibility to agricultural pesticides and non-Hodgkin lymphoma. Scand. J. Work Environ. Health 31 (Suppl. 1), 26–32 (2005).

    CAS  PubMed  Google Scholar 

  120. Crabb, D. W., 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. 63, 49–63 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Nowell, S. & Falany, C. N. Pharmacogenetics of human cytosolic sulfotransferases. Oncogene 25, 1673–1678 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Nioi, P. & Hayes, J. D. Contribution of NAD(P)H:quinone oxidoreductase-1 to protection against carcinogenesis, and regulation of its gene by the NRF2 basic-region leucine zipper and the aryl hydrocarbon receptor basic helix-loop-helix transcription factors. Mutat. Res. 555, 149–171 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Kiyohara, C., Yoshimasu, K., Takayama, K. & Nakanishi, Y. EPHX1 polymorphisms and the risk of lung cancer: a HuGE review. Epidemiology 17, 89–99 (2006).

    Article  PubMed  Google Scholar 

  124. Ye, Z. & Song, H. Glutathione S-transferase polymorphisms (GSTM1, GSTP1 and GSTT1) and the risk of acute leukemia: a systematic review and meta-analysis. Eur. J. Cancer 41, 980–989 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Lai, R., Crevier, L. & Thabane, L. Genetic polymorphisms of glutathione S-transferases and the risk of adult brain tumors: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 14, 1784–1790 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Maruo, Y., Iwai, M., Mori, A., Sato, H. & Takeuchi, Y. Polymorphism of UDP-glucuronosyltransferase and drug metabolism. Curr. Drug Metab. 6, 91–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Plastaras, J. P., Guengerich, F. P., Nebert, D. W. & Marnett, L. J. Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde. J. Biol. Chem. 275, 11784–11790 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Spiecker, M. & Liao, J. K. Vascular protective effects of cytochrome P450 epoxygenase-derived eicosanoids. Arch. Biochem. Biophys. 433, 413–420 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Bylund, J. & Oliw, E. H. Cloning and characterization of CYP4F21: a prostaglandin E2 20-hydroxylase of ram seminal vesicles. Arch. Biochem. Biophys. 389, 123–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Parmentier, J. H., Lavrentyev, E. N., Falck, J. R., Capdevila, J. H. & Malik, K. U. Evaluation of cytochrome P450 4 family as mediator of phospholipase D activation in aortic vascular smooth muscle cells. Life Sci. 77, 1015–1029 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Nebert, D. W. Inter-individual susceptibility to environmental toxicants — a current assessment. Toxicol. Appl. Pharmacol. 207, 34–42 (2005).

    Article  PubMed  CAS  Google Scholar 

  132. Xu, C., Li, C. Y. & Kong, A. N. Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch. Pharm. Res. 28, 249–268 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Tirona, R. G. & Kim, R. B. Nuclear receptors and drug disposition gene regulation. J. Pharm. Sci. 94, 1169–1186 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Klaassen, C. D. & Slitt, A. L. Regulation of hepatic transporters by xenobiotic receptors. Curr. Drug Metab. 6, 309–328 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Bookout, A. L. et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126, 789–799 (2006). One of the latest cutting-edge publications to describe receptors and their regulatory functions. A survey of the expression of all 49 mouse NR mRNAs in 39 tissues shows a hierarchical transcriptional circuitry that extends beyond individual tissues to form a mega-network that governs physiology on an organismal scale.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jandacek, R. J., Zheng, S., Yang, Q. & Tso, P. Rapid clearance of hexachlorobenzene from chylomicrons. Lipids 39, 993–995 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank our colleagues, especially L.F. Jorge-Nebert, for valuable discussions and careful readings of this manuscript. This work was funded in part by US National Institutes of Health grants.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniel W. Nebert.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute

lung cancer

FURTHER INFORMATION

Dan Nebert's homepage

Cytochrome P450 homepage

Human Cytochrome P450 Allele Nomenclature Committee

Indiana University Drug Interaction table

PharmGKB web site

HUGO gene nomenclature homepage

Glossary

Xenobiotic

A foreign chemical in the body. Any chemical, including drugs and foodstuffs, normally located outside the living organism, which exists in the organism (the opposite of an endogenous compound).

Eicosanoid

Any of the many physiologically active substances derived from arachidonic acid — including the prostaglandins, leuko-trienes, prostacyclins and thromboxanes — that are involved in many crucial life functions.

Inborn errors of metabolism

The term coined by A. Garrod in 1908 applying to heritable disorders of biochemistry. Examples include albinism and phenylketonuria.

Hydrophilic

To have a strong affinity for water, which is a property of polar molecules.

Reactive oxygenated intermediates

Chemicals, into which an atom of oxygen has been inserted. ROMs are relatively unstable and degrade quickly by reacting with, and binding covalently to, nucleic acids and proteins.

Genotoxicity

DNA damage. Many reactive oxygenated intermediates attack DNA, and either covalently bind to it to form adducts or produce oxidative stress, which can cause strand breaks and other chromosomal damage.

Xenobiotic-metabolizing enzymes

Enzymes that can metabolize a foreign chemical. It has been suggested that no XME exists for the metabolism of xenobiotics alone, that is, all XMEs have one or more endogenous substrates or functions. Often regulated by 'xenobiotic-sensing' receptors.

Xenobiotic-related transporters

Membrane-bound transporters that move endobiotics (and xenobiotics) across membranes, but which are also regulated by 'xenobiotic-sensing' receptors.

Pharmacokinetics

What the body does to a drug (or other exogenous chemical), encompassing absorption, distribution, metabolism and excretion. Sometimes called 'toxicokinetics'.

Pharmacodynamics

What a drug (or other exogenous chemical) does to the body, encompassing the biochemical and physiological effects and the mechanisms of drug or chemical action. Sometimes called 'toxicodynamics'.

Detoxication

Whereas various enzymes might be described as 'detoxifying a chemical substrate', R.T. Williams, in the 1940s, chose the term 'detoxication' to describe all detoxifying pathways in intact animals.

Procarcinogens

Chemicals capable of causing cancer, but which first require metabolic activation.

Electrophile

Molecules that are electron-deficient, and that are therefore attracted to other molecules (for example, nucleic acids and proteins) at a position where there is a net negative charge.

Hydrophobic

To have little affinity or to be repelled by water, a property of lipophilic ('fat loving') or nonpolar molecules.

Monogenic

Reflecting the properties of a single gene.

Penetrance

The penetrance of a gene refers to the proportion of individuals who, having a defined genotype, manifest a particular trait.

Multiplex phenotype

A trait caused by two or more genes and environmental factors.

Polycyclic aromatic hydrocarbons

Chemicals that contain only C and H atoms arranged in three or more rings (cycles), and that have conjugating double bonds (φ electrons), that is, not saturated. Benzo[α]pyrene (BaP) is a prototypic example. Found in industrial incineration products, cigarette smoke and charcoal-grilled food.

Aflatoxin B1

A potent toxin (C17H12O6) produced by the Aspergillus flavus group of fungi, which causes liver toxicity and cancer in mammals, birds and fish; it also causes mutations, birth defects and immunosuppression in animals. Found as a contaminant in peanuts, cottonseed meal, corn and other grains.

Polyhalogenated aromatic hydrocarbons

Chemicals comprised of C, H, and Cl, Br or F, and sometimes O atoms that are found in toxic waste dump sites and contaminated water; originating from insulators, combustion, refrigeration and other industrial processes. Polychlorinated biphenyls (PCBs) are a prototypic class of PHAHs. PHAHs can be either coplanar or non-coplanar.

Colupulone

The chemical in hops that gives beer its antibiotic properties.

Microsomes

An endoplasmic-reticulum-enriched preparation, produced by separating out cellular subfractions in an ultracentrifuge.

Ductus venosus

The blood vessel, located within the fetal liver, that connects (shunts) the umbilical vein to the inferior vena cava; at the time of birth, changes in the amount of oxygen in the blood and arterial–venous pressure normally close this shunt.

Methemoglobinemia

A condition in which the iron in the haemoglobin molecule (the red blood pigment) is oxidized, making it unable to carry oxygen effectively to the tissues.

Endobiotic

An endogenous compound. Any molecule that is normally expected to be located inside the organism (the opposite of xenobiotic).

Recombineering

The method by which highly efficient bacteriophage-based Escherichia coli homologous recombination sequences (as short as 35–50 bp) can enable genomic DNA in bacterial artificial chromosomes (BACs) to be modified and subcloned, without the need for restriction enzymes or DNA ligases. This new form of chromosome engineering is efficient and significantly reduces the time it takes to create transgenic mouse models compared with traditional methods.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nebert, D., Dalton, T. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6, 947–960 (2006). https://doi.org/10.1038/nrc2015

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2015

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing