Cytochrome P450 in Humans

  • F. J. Gonzalez
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 105)


This chapter will focus on the catabolic or foreign compound (xenobiotic)- metabolizing cytochromes P450 found in humans. Those cytochromes P450 involved in metabolic pathways leading to steroid synthesis will be thoroughly dealt with in other chapters of the handbook.


Human Cytochrome CYP2D6 Gene Human Liver Cytochrome CYP2C Subfamily CYP3A Cytochrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Aoyama T, Gonzalez FJ, Gelboin HV (1989a) Human cDNA-expressed cytochrome P450IA2: mutagen activation and substrate specificity. Mol Carcinog 2: 192–198PubMedCrossRefGoogle Scholar
  2. Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fisher V, Tyndale R, Inaba T, Kalow W, Gelboin HV, Gonzalez FJ (1989b) Cytochrome P-450 hPCN3, a novel cytochrome P-450IIIA gene product that is differentially expressed in adult human liver. J Biol Chem 264: 10388–10395PubMedGoogle Scholar
  3. Aoyama T, Yamano S, Guzelian PS, Gelboin HV, Gonzalez FJ (1990) Five of 12 forms of vaccinia virus-expressed human hepatic cytochrome P450 metabolically activate aflatoxin Bi. Proc Natl Acad Sci USA 87: 4790–4793PubMedCrossRefGoogle Scholar
  4. Bale AE, Mitchell AL, Gonzalez FJ, McBride OW (1991) Localization of the CYP2F1 gene by multi-point linkage analysis and pulsed field gel electrophoresis. Genomics 10: 284–286PubMedCrossRefGoogle Scholar
  5. Bargetzi MJ, Aoyama T, Gonzalez FJ, Meyer UA (1989) Lidocaine metabolism in human liver by cytochrome P450IIIA4 (PCN1). Clin Pharmacol Ther 46: 521–527PubMedCrossRefGoogle Scholar
  6. Beaune P, Dansette P, Flinois JP, Columelli S, Mansuy D, Leroux FP (1979) Partial purification of human liver cytochrome P-450. Biochem Biophys Res Commun 88: 826–832PubMedCrossRefGoogle Scholar
  7. Beaune PH, Umbenhauer DR, Bork RW, Lloyd RS, Guengerich FP (1986) Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase. Proc Natl Acad Sci USA 83: 8064–8068PubMedCrossRefGoogle Scholar
  8. Brian WR, Srivastava PK, Umbenhauer DR, Lloyd RS, Guengerich FP (1989) Expression of a human liver cytochrome P-450 protein with tolbutamide hydroxylase activity in Saccharomyces cerevisiae. Biochemistry 28: 4993–4999PubMedCrossRefGoogle Scholar
  9. Brian WR, Sari MA, Iwasaki M, Shimada T, Kaminsky LS, Guengerich FP (1990) Catalytic activities of human liver cytochrome P-450IIIA4 expressed in Saccharomyces cerevisiae. Biochemistry 29: 11280–11292PubMedCrossRefGoogle Scholar
  10. Broly F, Gaedigk A, Heim M, Eichelbaum M, Morike K, Meyer UA (1991) Debrisoquine hydroxylase genotype and phenotype. DNA Cell Biol 10: 545–558PubMedCrossRefGoogle Scholar
  11. Brooks BA, McBride OW, Dolphin CT, Farrall M, Scambler PJ, Gonzalez FJ, Idle JR (1988) The gene CYP3 encoding P45PCN1 (nifedipine oxidase) is tightly linked to the gene COLIA2 encoding collagen type I alpha on 7q21–p22.1. Am J Hum Genet 43: 280–284PubMedGoogle Scholar
  12. Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF (1989) 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 USA 86: 7696–7700PubMedCrossRefGoogle Scholar
  13. Butler MA, Lang NP, Young JF, Caporaso NE, Vineis P, Hayes RB, Teitel CH, Massengill JP, Lawsen MF, Kadlubar FF (1992) Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics 2: 116–127PubMedCrossRefGoogle Scholar
  14. Caporaso N, Landi MT, Vineis P (1991) Relevence of metabolic polymorphisms to human carcinogenesis: evolution of epidemiologic evidence. Pharmacogenetics 1: 4–19PubMedCrossRefGoogle Scholar
  15. Casazza JP, Felver ME, Veech RL (1984) The metabolism of acetone in rat. J Biol Chem 259: 231–236PubMedGoogle Scholar
  16. Chlerton S, Idle ME, Vas A, Gonzalez FJ, Idle JR (1992) Comparison of a novel thin-layer chromatography-fluorescence detection method with a spectrofluorometric method for the determination of 7-hydroxycoumarin in human urine. J Chromatog 575: 325–330CrossRefGoogle Scholar
  17. Conney AH (1982) Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G.H.A. Clowes Memorial Lecture. Cancer Res 42: 4875–4917PubMedGoogle Scholar
  18. Crespi CL, Thilly (1984) Assay for gene mutation in a lymphoblastoid cell line AHH-1, competent for xenobiotic metabolism. Mutat Res 128: 221–230Google Scholar
  19. Crespi C, Steimel DT, Aoyama T, Gelboin HV, Gonzalez FJ (1990a) Stable expression of human cytochrome P450IA2 cDNA in a human lymphoblastoid cell line: role of the enzyme in the metabolic activation of aflatoxin B1 Mol Carcinog 3: 5–8Google Scholar
  20. Crespi CL, Penman BW, Leakey JAE, Arlotto M, Stark A, Turner T, Steimel DT, Rudo K, Davies RL, Langenbach R (1990b) Human cytochrome P450IIA3: cDNA sequence role of the enzyme in the metabolic activation of promutagens: comparison to nitrosamine activation by human cytochrome P450IIE1. Carcinogenesis 11: 1293–1300PubMedCrossRefGoogle Scholar
  21. Crespi CL, Penman BW, Steimel DT, Gelboin HV, Gonzalez FJ (1991a) The development of a human cell line stably expressing human CYP3A4: role in the metabolic activation of aflatoxin B1 and comparison to CYP1A2 and CYP2A3. Carcinogenesis 12: 355–359PubMedCrossRefGoogle Scholar
  22. Crespi CL, Penman BW, Gelboin HV, Gonzalez FJ (1991b) A tobacco smoke- derived nitrosamine, 4-(methylnitrosamino)-l-(3-pyridyl)-l-butone (NNK), is activated by the polymorphic human cytochrome P4502D6 (CYP2D6). Carcinogenesis 12: 1197–1201PubMedCrossRefGoogle Scholar
  23. Daly AK, Armstrong M, Monkman SC, Idle ME, Idle JR (1991) Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes. Pharmacogenetics 1: 33–41PubMedCrossRefGoogle Scholar
  24. deWaziers I, Cugnenc P, Yang CS, Leroux JP, Beaune P (1990) Cytochrome P-450 isozymes, epoxide hydrolase and glutathione transferase in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther 253: 387–394Google Scholar
  25. Diaz D, Fabre I, Daujat M, Saint Aubert B, Bories P, Michel H, Maurel P (1990) Omeprazol is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 99: 737–747PubMedGoogle Scholar
  26. Distlerath LM, Guengerich FP (1987) Enzymology of human liver cytochromes P450. In: Guengerich FP (ed) Mammalian cytochromes P450, vol I. CRC Press, Boca Raton, p 133Google Scholar
  27. Distlerath LM, Reilly PEB, Martin MV, Davis GG, Wilkinson GR, Guengerich FP (1985) Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem 260: 9057–9067PubMedGoogle Scholar
  28. Eichelbaum M, Gross AS (1990) The genetic polymorphism of debrisoquine/sparteine metabolism-clinical aspects. Pharmacol Ther 46: 377–394PubMedCrossRefGoogle Scholar
  29. Eliasson E, Johansson I, Ingelman-Sundberg M (1990) Substrate-, hormone-, and cAMP-regulated cytochrome P450 degradation. Proc Natl Acad Sci USA 87: 3225–3229PubMedCrossRefGoogle Scholar
  30. Eugster HP, Sengstag C, Meyer UA, Hinnen A, Wurgler FE (1990) Constitutive and inducible expression of human cytochrome P450IA1 in yeast Saccharomyces cerevisiae: an alternative enzyme source for in vitro studies. Biochem Biophys Res Commun 172: 737–744PubMedCrossRefGoogle Scholar
  31. Fukuhara M, Nagata K, Mizukami K, Yamazoe Y, Takahaka A, Kato R (1989) Complete cDNA sequence of a major 3-methylcholanthrene-inducible cytochrome P-450 isozyme (P450AFB) of Syrian hamster with high activity toward aflatoxin Bi. Biochem Biophys Res Commun 162: 265–272PubMedCrossRefGoogle Scholar
  32. Furuya H, Meyer UA, Gelboin HV, Gonzalez FJ (1991) Polymerase chain reaction-directed identification, cloning and quantification of human CYP2C18 mRNA. Mol Pharmacol 40: 375–382PubMedGoogle Scholar
  33. Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA (1991) Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet 48: 943–950PubMedGoogle Scholar
  34. Ged C, Umbenhauer DR, Bellew TM, Bork RW, Srivastava PK, Shinriki N, Lloyd RS, Guengerich FP (1988) Characterization of cDNAs, mRNAs and proteins related to human liver microsomal cytochrome P-450 (S)-mephenytoin 4′-hydroxylase. Biochemistry 27: 6929–6940PubMedCrossRefGoogle Scholar
  35. Gonzalez FJ, Gelboin HV (1992) cDNA-directed expression of human cytochromes P450. In: Jeffrey EH (ed) Human drug metabolism: from molecular biology to man. CRC Press, Boca Raton, (in press).Google Scholar
  36. Gonzalez FJ, Meyer UA (1991) Molecular genetics of the debrisoquine/sparteine polymorphism. Clin Pharmacol Ther 50: 233–238PubMedCrossRefGoogle Scholar
  37. Gonzalez FJ, Nebert DW (1990) Evolution of the P450 superfamily: animal-plant “warfare”, molecular drive and human genetic differences in drug oxidation. Trends Genet 6: 182–187.PubMedCrossRefGoogle Scholar
  38. Gonzalez FJ, Song BJ, Hardwick JP (1986) Prenenoline 16α-carbinitrile-inducible P-450 gene family: gene conversion and differential regulation. Mol Cell Biol 6: 2969–2976PubMedGoogle Scholar
  39. Gonzalez FJ, Schmid BJ, Umeno M, McBride OW, Hardwick FP, Meyer UA, Gelboin HV, Idle JR (1988a) Human P450PCN1: sequence, chromosome localization and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA 7: 74–86CrossRefGoogle Scholar
  40. Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin HV, Hardwick JP, Meyer UA (1988b) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331: 442–446PubMedCrossRefGoogle Scholar
  41. Gonzalez FJ, Vilbois F, Hardwick JP, McBride OW, Nebert DW, Gelboin HV, Meyer UA (1988c) Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics 2: 174–179PubMedCrossRefGoogle Scholar
  42. Gonzalez FJ, Matsunaga T, Nagata K (1989) Structure and regulation of P450s in the rat P450IIA gene subfamily. Drug Metab Rev 20: 827–837PubMedCrossRefGoogle Scholar
  43. Gonzalez FJ, Crespi CL, Gelboin HV (1991a) cDNA-expressed human cytochrome P450: a new age of molecular toxicology and human risk assessment. Mutat Res 247: 113–127Google Scholar
  44. Gonzalez FJ, Ueno T, Umeno M, Song BJ, Veech RL, Gelboin HV (1991b) Microsomal ethanol oxidizing system: transcriptional and posttranscriptional regulation of cytochrome P450 CYP2E1. In: Kalant H, Khanna JM, Israel Y (eds) Advances in biomedical alcohol research. Pergamon, New York, pp 97–101Google Scholar
  45. Gu L, Gonzalez FJ, Kalow W, Tang BK (1992) Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed CYP1A2 and CYP2E1. Pharmacogenetics 2: 73–77PubMedCrossRefGoogle Scholar
  46. Guengerich FP (1987) Enzymology of rat liver cytochromes P450. In: Guengerich FP (ed) Mammalian cytochromes P450, vol I. CRC Press, Boca Raton, p 1Google Scholar
  47. Guengerich FP, Kim DH (1990) In vitro inhibition of dihydropyridine oxidation and aflatoxin Bi activation in human liver microsomes by naringin and other flavenoids. Carcinogenesis 11: 2275–2279PubMedCrossRefGoogle Scholar
  48. Guengerich FP, Shimada T (1991) Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem Res Toxicol 4: 391–407PubMedCrossRefGoogle Scholar
  49. Guengerich FP, Marin MV, Beaune PH, Kremers P, Wolff T, Waxman DJ (1986) 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 261: 5051–5060PubMedGoogle Scholar
  50. Guengerich FP, Kim DH, Iwasaki M (1991) Role of human cytochrome P450IIE1 in the oxidation of several low molecular weight cancer suspects. Chem Res Toxicol 4: 168–179PubMedCrossRefGoogle Scholar
  51. Gut J, Meier UT, Catin T, Meyer UA (1986) Mephenytoin-type polymorphism of drug oxidation: purification and characterization of a human liver cytochrome P-450 isozyme catalyzing microsomal mephenytoin hydroxylation. Biochim Biophys Acta 884: 435–447PubMedCrossRefGoogle Scholar
  52. Hanioka N, Kimura S, Meyer UA, Gonzalez FJ (1990) The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934 A base change in intron 3 of mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am J Hum Genet 47: 994–1001PubMedGoogle Scholar
  53. Heim MH, Meyer UA (1990) Genotyping of poor metabolizers of debrisoquine by allele-specific PCR amplification. Lancet 336: 529–532PubMedCrossRefGoogle Scholar
  54. Heim M, Beer M, Meyer UA (1992) Evolution of a highly polymorphic human gene: CYP2D6. Genomics (in press)Google Scholar
  55. Hildebrand CE, Gonzalez FJ, McBride OW, Nebert DW (1985) Assignment of the human 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible cytochrome Pr450 gene to chromosome 15. Nucleic Acids Res 13: 2009–2016PubMedCrossRefGoogle Scholar
  56. Imaoka S, Terano Y, Funae Y (1988) Constitutive testosterone 6ß-hydroxylase in rat liver. J Biochem 104: 481–487PubMedGoogle Scholar
  57. Jaiswal AK, Gonzalez FJ, Nebert DW (1985a) Human dioxin-inducible cytochrome Pr450: complementary DNA and amino acid sequence. Science 228: 80–85PubMedCrossRefGoogle Scholar
  58. Jaiswal AK, Gonzalez FJ, Nebert DW (1985b) Human Pr450 gene sequence and correlation of mRNA with genetic differences in benzo[a]pyrene metabolism. Nucleic Acids Res 13: 4503–4520PubMedCrossRefGoogle Scholar
  59. Jaiswal AK, Nebert DW, Eisen HW (1985c) Comparison of arylhydrocarbon hydroxylase and acetanilide 4-hydroxylase induction by polycyclic aromatic compounds in human and mouse cell lines. Biochem Pharmacol 34: 2721–2731PubMedCrossRefGoogle Scholar
  60. Jaiswal AK, Nebert DW, McBride OW, Gonzalez FJ (1987) Human P3-450: cDNA and complete protein sequence, repeitive Alu sequences in the 3′ nontranslated region, and localization of gene to chromosome 15. J Exp Pathol 3: 1–17PubMedGoogle Scholar
  61. Kagimoto M, Heim M, Kagimoto K, Zeutin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine: study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 265: 17209–17216PubMedGoogle Scholar
  62. Kawajiri K, Watanabe J, Gotoh O, Tagashira Y, Sogawa K, Fujii-Kuriyama Y (1986) Structure and drug inducibility of the human cytochrome P-450c gene. Eur J Biochem 159: 219–225PubMedCrossRefGoogle Scholar
  63. Kawajiri K, Nakachi K, Imai K, Yoshii A, Shinoda N, Watanabe J (1990) Identification of genetically high risk individual to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene. FEBS Lett 263: 131–133PubMedCrossRefGoogle Scholar
  64. Kawajiri K, Nakachi K, Imai K, Hayashi S, Watanabe J (1991) The individual difference of susceptibility to lung cancer in relation to polymorphisms of P450IA1 gene and cigarette dose. In: Ernster L, Gelboin HV, Sugimura T (eds) Xenobiotics and cancer. Japan Society, Tokyo; Taylor and Francis, London, pp 55–61Google Scholar
  65. Kimura S, Pastekwa J, Gelboin HV, Gonzalez FJ (1987) cDNA and amino acid sequences of two members of the human P450IIC gene subfamily. Nucleic Acids Res 15: 10053–10054Google Scholar
  66. Kimura S, Kozak CA, Gonzalez FJ (1989a) Identification of a novel P450 expressed in rat lung: cDNA cloning and sequence, chromosome mapping, and induction by 3-methylcholanthrene. Biochemistry 28: 3798–3803PubMedCrossRefGoogle Scholar
  67. Kimura S, Umeno M, Skoda R, Meyer UA, Gonzalez FJ (1989b) The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene and a pseudogene. Am J Hum Genet 45: 889–904PubMedGoogle Scholar
  68. Kitada M, Kamataki T (1979) Partial purification and properties of cytochrome P450 from homogenates of human fetal livers. Biochem Pharmacol 28: 793–797PubMedCrossRefGoogle Scholar
  69. Kitada M, Kamataki T, Itahashi K, Rikihisa T, Kato R, Kanakubo Y (1985) Purification and properties of cytochrome P-450 from homogenates of human fetal livers. Arch Biochem Biophys 241: 275–280PubMedCrossRefGoogle Scholar
  70. Komori M, Nishio K, Ohi H, Kitada M, Kamataki T (1989) Molecular cloning and sequence analysis of cDNA containing the entire coding region for human fetal liver cytochrome P-450. J Biochem (Tokyo) 185: 161–163Google Scholar
  71. Koop DR, Casazza JP (1985) Identification of ethanol-inducible P-450 isozyme 3α as the acetone and acetol monooxygenase of rabbit microsomes. J Biol Chem 260: 13607–13612PubMedGoogle Scholar
  72. Kronbach T, Fisher V, Meyer UA (1988) Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporin-metabolizing enzyme explains interactions of cyclosporine with othe drugs. Clin Pharmacol Ther 43: 630–635PubMedCrossRefGoogle Scholar
  73. Kronbach T, Mathys D, Umeno M, Gonzalez FJ, Meyer UA (1989) Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 36: 89–96PubMedGoogle Scholar
  74. Lambert GH, Schoeller DA, Humphrey HE, Kotake AN (1990) The caffeine breath test and caffeine urinary metabolite ratios in the Michigan cohort exposed to polybrominated biphenyls: a preliminary study. Environ Health Perspect 89: 175–181PubMedCrossRefGoogle Scholar
  75. Lucey MR, Kolars JC, Merion RM, Campbell DA, Aldrich M, Watkins PB (1990) Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 III A. Lancet 335: 11–15PubMedCrossRefGoogle Scholar
  76. Maurice M, Emiliani S, Dalet-Beluche I, Derancourt J, Lange R (1991) Isolation and characterization of a cytochrome P450 of the IIA subfamily from human liver microsomes. Eur J Biochem 200: 511–517PubMedCrossRefGoogle Scholar
  77. McLemore T, Adelberg S, Liu MC, McMahon NA, Yu SJ, Hubbard WC, Czerwinski M, Coudert BP, Moscow JA, Stinson S, Storeng R, Lubet RA, Eggleston JC, Boyd MR, Hines RN (1990) Cytochrome P450IA1 gene expression in lung cancer patients: evidence for cigarette smoke-induced expression in normal lung and altered gene regulation in primary pulmonary carcinomas. JNCI 82: 1333–1339PubMedGoogle Scholar
  78. McManus ME, Stupans I, Ioanni B, Burgess W, Robson RA, Birkett DJ (1988) Identification and quantitation in human liver of cytochromes P-450 analogous to rabbit cytochromes P-450 forms 4 and 6. Xenobiotica 18: 207–216PubMedCrossRefGoogle Scholar
  79. McManus ME, Burgess WM, Veronese ME, Huggett A, Quattrochi LC, Tukey RH (1990) Metabolism of 2-acetylaminogluroene and benzo[a]pyrene and activation of food-derived heterocyclic amine mutagens by human cytochromes P-450. Cancer Res 50: 3367–3376PubMedGoogle Scholar
  80. Meehan RR, Gosden JR, Rout D, Hastie ND, Friedberg T, Adesnik M, Buckland R, vanHeyningen V, Fletcher J, Spurr NK, Sweeney J, Wolf CR (1988) Human cytochrome P-450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Hum Genet 42: 26–37PubMedGoogle Scholar
  81. Meyer UA, Skoda RC, Zanger UM (1990) The genetic polymorphism of debrisoquine/sparteine metabolism-molecular mechanisms. Pharmacol Ther 46: 297–308PubMedCrossRefGoogle Scholar
  82. Miles JS, Spurr NK, Gough AC, Jowett T, McLaren AW, Brook JD, Wolf CR (1988) A novel human cytochrome P450 gene (P450IIB): chromosomal localization and evidence for alternative splicing. Nucleic Acids Res 16: 5783–5794PubMedCrossRefGoogle Scholar
  83. Miles JS, Bickmore W, Brook JD, McLaren AW, Meehan R, Wolf CR (1989) Close linkage of the human cytochrome P450IIA and P450IIB gene subfamilies: implication for the assignment of substrate specificity. Nucleic Acids Res 17: 2907–2917PubMedCrossRefGoogle Scholar
  84. Miles JS, McLaren AW, Forrester LM, Glancey MJ, Lang MA, Wolf CR (1990) Identification of the human liver cytochrome P-450 responsible for coumarin 7-hydroxylase activity. Biochem J 267: 365–371PubMedGoogle Scholar
  85. Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS (1986) Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci USA 83: 5311–5315PubMedCrossRefGoogle Scholar
  86. Nebert DW (1989) The Ah locus: genetic differences in toxicity, cancer, mutation and birth defects. Curr Rev Tox 20: 153–174CrossRefGoogle Scholar
  87. Nebert DW (1991a) Polymorphism of human CYP2D6 genes involved in drug metabolism: possible relationship to individual cancer risk. Cancer Cells 3: 93–96PubMedGoogle Scholar
  88. Nebert DW (1991b) Proposed role of drug-metabolizing enzymes: regulation of steady-state levels of the ligands that affect growth, homeostasis, differentiation and neuroendocrine functions. Mol Endocrinol 5: 1203–1214PubMedCrossRefGoogle Scholar
  89. Nebert DW, Nelson DR, Feyereisen R (1989) Evolution of the cytochrome P450 genes. Xenobiotica 19: 1149–1160PubMedCrossRefGoogle Scholar
  90. Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R, Fujii-Kuriyama Y, Gonzalez FJ, Guengerich FP, Gunsalus IC, Johnson EF, Loper JC, Sato R, Waterman MR, Waxman DJ (1991) The P450 superfamily: update on new sequences, gene mapping and recommended nomenclature. DNA Cell Biol 10: 1–14PubMedCrossRefGoogle Scholar
  91. Nhamburo PT, Gonzalez FJ, McBride OW, Gelboin HV, Kimura S (1989) Identification of a new P450 expressed in human lung: complete cDNA sequence, cDNA-directed expression, and chromosome mapping. Biochemistry 28: 8060–8066PubMedCrossRefGoogle Scholar
  92. Nhamburo PT, Kimura S, McBride OW, Kozak CA, Gelboin HV, Gonzalez FJ (1990) The human CYP2F gene subfamily: identification of a cDNA-encoding a new cytochrome P450, cDNA-directed expression, and chromosome mapping. Biochemistry 29: 5491–5499PubMedCrossRefGoogle Scholar
  93. Okino ST, Quattrochi LC, Pendurthi UR, McBride OW, Tukey RH (1987) Characterization of multiple human cytochrome P4501 cDNAs: the chromosomal localization of the gene and evidence for alternative splicing. J Biol Chem 262: 16072–16079PubMedGoogle Scholar
  94. Peter R, Bocker RG, Beaune PH, Iwasaki M, Guengerich FP, Yang CS (1990) Hydroxylation of chlorzoxazone as a specific probe for human liver cytochrome P450IIE1. Chem Res Toxicol 3: 566–573PubMedCrossRefGoogle Scholar
  95. Petersen DD, McKinney CE, Ikeya K, Smith HH, Bale AE, McBride OW, Nebert DW (1991) Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and a restriction fragment length polymorphism. Am J Hum Genet 48: 720–725PubMedGoogle Scholar
  96. Phillips IR, Shephard EA, Ashworth A, Rabin BP (1985a) Isolation and sequence of a human cytochrome P-450 cDNA clone. Proc Natl Acad Sci USA 82: 983–987PubMedCrossRefGoogle Scholar
  97. Phillips IR, Shephard EA, Povey S, Davis MB, Kelsey G, Monteiro M, West LF, Cowell J (1985b) A cytochrome P-450 gene family mapped to human chromosome 19. Ann Hum Genet 49: 207–274CrossRefGoogle Scholar
  98. Quattrochi LC, Tukey RT (1990) Human cytochrome P450IA2 contains tissue specific regulatory elements responsive to 3-methylcholanthrene. Mol Pharmacol 36: 66–71Google Scholar
  99. Quattrochi LC, Pendurthi UR, Okino ST, Potenza C, Tukey RT (1986) Human cytochrome P-450 4 mRNA and gene: part of a multigene family that contains Alu sequences in its mRNA. Proc Natl Acad Sci USA 83: 6731–6735PubMedCrossRefGoogle Scholar
  100. Raucy JL, Lasker JM, Lieber CS, Black M (1989) Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Arch Biochem Biophys 271: 270–283PubMedCrossRefGoogle Scholar
  101. Relling MV, Aoyama T, Gonzalez FJ, Meyer UA (1990) Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. J Pharmacol Exp Ther 252: 442–447PubMedGoogle Scholar
  102. Renaud JP, Cullin C, Pompon D, Beaune P, Mansuy D (1990) Expression of human liver cytochrome P450 IIIA4 in yeast: a functional model for the hepatic enzyme. Eur J Biochem 194: 884–886CrossRefGoogle Scholar
  103. Rettie AE, Korzekwa K, Kunze KL, Lawrence RF, Eddyll AC, Aoyama T, Gelboin HV, Gonzalez FJ, Trager WF (1991) Hydroxylation of warfarin by human liver cytochrome P450: a role for proteins encoded by CYP2C9 in the etiology of anticoagulant drug interactions. Mol Pharmacol (in press)Google Scholar
  104. Ritter JK, Owens IS, Negishi M, Nagata K, Sheen YY, Gillette JR, Sasame HA (1991) Mouse pulmonary cytochrome P450 napthalene hydroxylase: cDNA cloning sequence and expression in Saccharomyces cerevisiae. Biochemistry 30: 11430–11437PubMedCrossRefGoogle Scholar
  105. Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA (1991) Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry 30: 3247–3255PubMedCrossRefGoogle Scholar
  106. Ryan DE, Levin W (1990) Purification and characterization of hepatic microsomal P-450. Pharmacol Ther 45: 153–239PubMedCrossRefGoogle Scholar
  107. Santisteban I, Povey S, Shephard EA, Phillips IR (1988) The major phenobarbital-inducible cytochrome P-450 gene subfamily (P450IIB) mapped to the long arm of human chromosome 19. Ann Hum Genet 52: 129–135PubMedCrossRefGoogle Scholar
  108. Schwab GE, Johnson EF (1987) Enzymology and rabbit cytochromes P450. In: Guengerich FP (ed) Mammalian cytochromes P450, vol I. CRC Press, Boca Raton, p 55Google Scholar
  109. Shephard EA, Phillips IR, Santisteban I, Palmer CNA, Povey S (1987) Cloning, expression and chromosomal localization of a member of the human cytochrome P450IIC gene sub-family. Ann Hum Genet 53: 23–31CrossRefGoogle Scholar
  110. Shimada T, Guengerich FP (1989) 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 USA 86: 462–465PubMedCrossRefGoogle Scholar
  111. Shimada T, Misono KS, Guengerich FP (1986) Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism: purification and characterization of two similar forms involved in the reaction. J Biol Chem 261: 909–921PubMedGoogle Scholar
  112. Shimada T, Iwasaki M, Martin MV, Guengerich FP (1989) Human liver microsomal cytochromes P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA1535/pSkl002. Cancer Res 49: 3218–3228PubMedGoogle Scholar
  113. Smith CAD, Gough AC, Leigh PN, Summers BA, Harding AE, Maranganore DM, Sturman SG, Schapira AHV, Williams AC, Spurr NK, Wolf CR (1992) Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson’s disease. Lancet 339: 1375–1377PubMedCrossRefGoogle Scholar
  114. Song BJ, Gelboin HV, Park SS, Yang CS, Gonzalez FJ (1986) Complimentary DNA and protein sequences of ethanol-inducible rat and human P-450: transcriptional and posttranscriptional regulation of the rat enzyme. J Biol Chem 261: 16689–16697PubMedGoogle Scholar
  115. Song BJ, Veech RL, Park SS, Gelboin HV, Gonzalez FJ (1989) Induction of rat hepatic 7V-nitrosodimethylamine demethylase by acetone is due to protein stabilization. J Biol Chem 264: 3568–3572PubMedGoogle Scholar
  116. Srivastava PK, Yun SH, Beaune PH, Ged C, Guengerich FP (1991) Separation of human liver microsomal tolbutamide hydroxylase and (S)-mephenytoin 4′- hydroxylase cytochrome P-450 enzymes. Mol Pharmacol 40: 69–79PubMedGoogle Scholar
  117. Tang BK, Kadar D, Qian L, Iriah J, Yip J, Kalow W (1991) Caffeine as a metabolic probe: validation of its use for acetylator phenotyping. Clin Pharm Ther 49: 648–657CrossRefGoogle Scholar
  118. Tefre T, Ryberg D, Haugen A, Nebert DW, Skaug V, Brogger A, Borresen AL (1991) Human CYP1A1 (cytochrome P1450) gene: lack of association between Msp I restriction fragment length polymorphism and incidence of lung cancer in a Norwegian population. Pharmacogenetics 1: 20–25PubMedCrossRefGoogle Scholar
  119. Ueno T, Gonzalez FJ (1990) Transcriptional control of the rat hepatic CYP2E 1 gene. Mol Cell Biol 10: 4495–4505PubMedGoogle Scholar
  120. Umbenhauer DR, Martin MV, Lloyd RS, Guengerich FP (1987) Cloning and sequence determination of a complementary DNA related to human liver microsomal cytochrome P-450 S-mephenytoin 4-hydroxylase. Biochemistry 26: 1094–1099PubMedCrossRefGoogle Scholar
  121. Umeno M, McBride OW, Yang CS, Gelboin HV, Gonzalez FJ (1988a) Human ethanol-inducible P450IIE1: complete gene sequence, promoter characterization, chromosome mapping, regulation and cDNA-directed expression. Biochemistry 27: 9000–9013CrossRefGoogle Scholar
  122. Umeno M, Song BJ, Kozak C, Gelboin HV, Gonzalez FJ (1988b) The rat P450IIE1 gene: complete intron and exon sequence, chromosome mapping, and correlation of developmental expression with specific 5′ cytosine demethylation. J Biol Chem 263: 4956–4962PubMedGoogle Scholar
  123. Vistisen K, Poulsen HE, Loft S (1992) Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. Carcinogenesis 13: 1561–1568PubMedCrossRefGoogle Scholar
  124. Watkins PB, Wrighton PB, Schuetz EG, Molowa DT, Guzelian PS (1987) Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest 80: 1029–1036PubMedCrossRefGoogle Scholar
  125. Watkins PB, Murray SA, Wilkelman LG, Heuman DM, Wrighton SA, Guzelian PS (1989) Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. J Clin Invest 83: 688–697PubMedCrossRefGoogle Scholar
  126. Wilkinson GR, Guengerich FP, Branch RA (1989) Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 43: 53–76PubMedCrossRefGoogle Scholar
  127. Wrighton SA, Vandenbranden M (1989) Isolation and characterization of human fetal liver cytochrome P450HLP2: a third member of the P450III gene family. Arch Biochem Biophys 268: 144–151PubMedCrossRefGoogle Scholar
  128. Wrighton SA, Campanile C, Thomas PE, Maines SL, Watkins PB, Parker G, Mendez-Picon G, Haniu M, Shively JE, Levin W, Guzelian PS (1986) Identification of a human liver cytochrome P-450 homologous to the major isosafrole-inducible cytochrome P-450 in the rat. Mol Pharmacol 29: 405–410PubMedGoogle Scholar
  129. Wrighton SA, Thomas PE, Ryan DE, Levin W (1987) Purification and characterization of ethanol-inducible human hepatic cytochrome P-450HLj. Arch Biochem Biophys 258: 292–297PubMedCrossRefGoogle Scholar
  130. Wrighton SA, Ring BJ, Watkins PB, Vandenbranden M (1989) Identification of a polymorphically expressed member of the human cytochrome P-450III family. Mol Pharmacol 36: 97–105PubMedGoogle Scholar
  131. Yamano S, Nhamburo PT, Aoyama T, Meyer UA, Inaba T, Kalow W, Gelboin HV, McBride OW, Gonzalez FJ (1989) cDNA cloning and sequence and cDNA-directed expression of human P450 IIB1: identification of a normal and two variant cDNAs derived from the CYP2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver. Biochemistry 28: 7340–7348Google Scholar
  132. Yamano S, Tatsuno J, Gonzalez FJ (1990) The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. Biochemistry 29: 1322–1329PubMedCrossRefGoogle Scholar
  133. Yasumori T, Kawano S, Nagata K, Shimada M, Yamazoe Y, Kato R (1987) Nucleotide sequence of a human liver cytochrome P450 related to the rat male specific form. J Biochem (Tokyo) 102: 1075–1082Google Scholar
  134. Yasumori T, Murayama N, Yamazoe Y, Kato R (1989) Polymorphism in hydroxylation of mephenytoin and hexobarbital stereoisomers in relation to hepatic P-450 human-2. Clin Pharmacol Ther 47: 313–322CrossRefGoogle Scholar
  135. Yun CH, Shimada T, Guengerich FP (1991) Purification and characterization of human liver microsomal P-4502A6. Mol Pharmac 40: 679–685Google Scholar

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© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • F. J. Gonzalez

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