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Genetics: Animal and Human Cytochrome P450 Polymorphisms

  • A. K. Daly
  • J. R. Idle
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 105)

Abstract

There is now considerable evidence for wide interindividual variation in cytochrome P450 activity in both humans and animals. This variation may be due to a genetic polymorphism which results in either lack of protein synthesis or synthesis of a protein with reduced enzyme activity or to variation in the level of cytochrome P450 gene expression due to regulation by factors such as hormones or xenobiotics. In this chapter, the effect of polymorphisms in cytochrome P450 genes on enzyme activity in the microsomal drug-metabolising cytochrome P450 families 1 to 3 will be considered.

Keywords

Poor Metabolisers Restriction Fragment Length Polymorphism Analysis Dark Agouti Cytochrome P450 Gene Human Liver 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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References

  1. Ahsan CH, Renwich AG, Macklin B, Challenor VF, Waller DG, George CF (1991) Ethnic differences in the pharmacokinetics of oral nifedipine. Br J Clin Pharmacol 31: 399–403PubMedGoogle Scholar
  2. Al-Dabbagh SG, Idle JR, Smith RL (1981) Animal modelling of human polymorphic drug oxidation — the metabolism of debrisoquine and phenacetin in rat inbred strains. J Pharm Pharmacol 33: 161–164PubMedCrossRefGoogle Scholar
  3. Alvan G, Bechtel P, Iselius L, Gundert-Remy U (1990) Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 39: 533–537PubMedCrossRefGoogle Scholar
  4. Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fischer V, Tyndale R, Inaba T, Kalow W, Gelboin HV, Gonzalez FJ (1989) Cytochrome P450 hPCN3, a novel cytochrome P450 III A gene product that is differentially expressed in adult human liver. J Biol Chem 264: 10388–10395PubMedGoogle Scholar
  5. Ayesh R, Idle JR, Ritchie JC, Crothers MJ, Hetzel MR (1984) Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature 311: 169–170CrossRefGoogle Scholar
  6. Benitez J, Ladero JM, Jimenez-Jimenez FJ, Martinez C, Puerto AM, Valdivielso MJ, Llerena A, Cobaleda J, Munoz JJ (1990) Oxidation polymorphism of debrisoquine in Parkinson’s disease, J Neurol Neurosurg Psychiatry 53: 289–292PubMedCrossRefGoogle Scholar
  7. Benitez J, Ladero JM, Jara C, Carrillo JA, Cobaleda J, Llerena A, Vargas E, Munoz JJ (1991) Polymorphic oxidation of debrisoquine in lung cancer patients. Eur J Cancer 27: 158–161PubMedCrossRefGoogle Scholar
  8. Bertilsson L, Dengler HJ, Eichelbaum M, Schultz HU (1980) Pharmacokinetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. Eur J Clin Pharmacol 17: 153–155PubMedCrossRefGoogle Scholar
  9. Brian WR, Srivastava PK, Umbenhauer DR, Lloyd RS, Guengerich FP (1989) Expression of a human liver cytochrome P450 protein with tolbutamide hydroxylase activity in Saccharomyces cerevisiae. Biochemistry 28: 4993–4999PubMedCrossRefGoogle Scholar
  10. Brosen K, Gram LF (1989) Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 36: 537–547PubMedCrossRefGoogle Scholar
  11. Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF (1989) Human cytochrome P450PA (P450IA2), 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
  12. Caporaso NE, Tucker MA, Hoover RN, Hayes RB, Pickle LW, Issaq HJ, Muschik GM, Green-Gallo L, Buivys D, Aisner S, Resau JH, Trump BF, Tollerud D, Weston A, Harris CC (1990) Lung cancer and the debrisoquine metabolic phenotype. JNCI 82: 1264–1272PubMedGoogle Scholar
  13. Crespi CL, Penman BW, Gelboin HV, Gonzalez FJ (1991) A tobacco smoke-derived nitrosamine 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone, is activated by multiple human cytochrome P450s including the polymorphic human cytochrome P4502D6. Carcinogenesis 12: 1197–1201PubMedCrossRefGoogle Scholar
  14. Daly AK, Armstrong M, Monkman SC, Idle ME, Idle JR (1991) The genetic and metabolic criteria for the assignment of debrisoquine hydroxylation (cytochrome P450IID6) phenotypes. Pharmacogenetics 1: 33–41PubMedCrossRefGoogle Scholar
  15. Davis GC, Willians AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ (1979) Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1: 249–254PubMedCrossRefGoogle Scholar
  16. Dayer P, Balant L, Courvoisier F, Kupfer A, Kubli A, Gorgia A, Fabre J (1982) The genetic control of bufuralol metabolism in man. Eur J Drug Metab Pharmacokinet 7: 73–77PubMedCrossRefGoogle Scholar
  17. Distelrath LM, Reilly PEB, Martin MV, Davis GG, Wilkinson GR, Guengerich FP (1985) Purification and characterisation of the human liver cytochromes P450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem 260: 9057–9067Google Scholar
  18. Duche J-C, Joanne C, Barre J, de Cremoux H, Dalphin JC, Depierre A, Brochard P, Tillement JP, Bechtel P (1991) Lack of a relationship between the polymorphism of debrisoquine oxidation and lung cancer. Br J Clin Pharmacol 31: 533–536PubMedGoogle Scholar
  19. Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 17: 153–155Google Scholar
  20. Evans DAP, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study of the genetic polymorphism of debrisoquine oxidation in a British white population. J Med Genet 17: 102–105PubMedCrossRefGoogle Scholar
  21. Evans WE, Relling MV (1990) Xbal 16- plus 9-kilobase DNA restriction fragments identify a mutant allele for debrisoquin hydroxylase: report of a family study. Mol Pharmacol 37: 639–642PubMedGoogle Scholar
  22. Fonne-Pfister R, Bargetzi MJ, Meyer UA (1987) MPTP, the neurotoxin inducing Parkinson’s disease, is a potent competitive inhibitor of human and rat cytochrome P450 isozymes (P450bufl, P450dbl) catalysing debrisoquine 4-hydroxylation. Biochem Biophys Res Commun 148: 1144–1150PubMedCrossRefGoogle Scholar
  23. Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA (1991) Deletion of the entire cytochrome P450 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet 48: 943–950PubMedGoogle Scholar
  24. Ged C, Umbenhauer DR, Beilew TM, Bork RW, Srivastava PK, Shinriki N, Lloyd RS, Guengerich FP (1988) Characterisation of cDNAs, mRNAs, and proteins related to human liver microsomal cytochrome P450 (S)-mephenytoin 4-hydroxylase. Biochemistry 27: 6929–6940PubMedCrossRefGoogle Scholar
  25. Gonzalez FJ, Nebert DW (1990) Evolution of the P450 gene superfamily. Trends Genet 6: 182–186PubMedCrossRefGoogle Scholar
  26. Gonzalez FJ, Matsunaga T, Nagata K, Meyer UA, Nebert DW, Pastewka J, Kozak CA, Gillette J, Gelboin HV, Hardwick JP (1987) Debrisoquine 4-hydroxylase: characterisation of a new P450 gene subfamily, regulation, chromosomal mapping and molecular analysis of the DA rat polymorphism. DNA 6: 149–161PubMedCrossRefGoogle Scholar
  27. Gonzalez FJ, Schmid BJ, Umeno M, McBride OW, Hardwick JP, Meyer UA, Gelboin HV, Idle JR (1988a) Human P450PCN1: sequence, chromosomal localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA 7: 79–86PubMedCrossRefGoogle Scholar
  28. Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin HV, Hardwick JP, Meyer UA (1988b) Characterisation of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331: 442–446PubMedCrossRefGoogle Scholar
  29. 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
  30. Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, Wolf CR (1990) Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347: 773–776PubMedCrossRefGoogle Scholar
  31. Gudjonsson O, Sanz E, Alvan G, Aquilonius S-M, Reviriego J (1990) Poor hydroxylator phenotypes of debrisoquine and S-mephenytoin are not over-represented in a group of patients with Parkinson’s disease. Br J Clin Pharmacol 30: 301–302PubMedGoogle Scholar
  32. Hanioka N, Kimura S, Meyer UA, Gonzalez FJ (1990) The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934 to A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am J Hum Genet 47: 994–1001PubMedGoogle Scholar
  33. Heim M, Meyer UA (1990) Genotyping of poor metabolisers by allele-specific PCR amplification. Lancet 2: 529–532CrossRefGoogle Scholar
  34. Hoyo-Vadillo C, Castenada-Hernandez G, Herrera JE, Vidal-Garate J, Moreno- Ramos A, Chavez F, Hong E (1989) Pharmacokinetics of nifedipine slow release tablets in Mexican patients: further evidence for an oxidation polymorphism. J Clin Pharmacol 29: 816–820PubMedGoogle Scholar
  35. Inaba T, Lucassen M, Kalow W (1980) Antipyrine metabolism in the rat by three monooxygenases. Life Sci 26: 1977–1983PubMedCrossRefGoogle Scholar
  36. Johansson I, Yue QY, Dahl ML, Heim M, Sawe J, Bertilsson L, Meyer UA, Sjoqvist F, Ingelman-Sundberg M (1991) Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine. Eur J Clin Pharmacol 40: 553–556PubMedGoogle Scholar
  37. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolisers of debrisoquine. J Biol Chem 265: 17209–17214PubMedGoogle Scholar
  38. Kahn GC, Roubenfield M, Davies DS, Murray S, Boobis AR (1985) Sex and strain differences in hepatic debrisoquine 4-hydroxylase activity of the rat. Drug Metab Dispos 13: 510–516PubMedGoogle Scholar
  39. Kawagiri K, Nakachi K, Imai K, Yoshii A, Shinoda N, Watanabe J (1990) Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene. FEBS Lett 263: 131–133CrossRefGoogle Scholar
  40. Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ (1989) The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of a polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet 45: 889–905PubMedGoogle Scholar
  41. Kleinbloesem C, van Brummelen P, Faber H, Danhof M, Vermeulen NP, Breimer DD (1984) Variability in nifedipine kinetics and dynamics: a new oxidation polymorphism in man. Biochem Pharmacol 33: 3721–3724PubMedCrossRefGoogle Scholar
  42. Küpfer A, Preisig R (1984) Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 26: 753–759PubMedCrossRefGoogle Scholar
  43. Küpfer A, Roberts RK, Schenker S, Branch RA (1981) Stereoselective metabolism of mephenytoin in man. J Pharmacol Exp Ther 218: 193–199PubMedGoogle Scholar
  44. Küpfer A, Dick B, Preisig R (1982) A new drug hydroxylation polymorphism in man: the incidence of mephenytoin hydroxylation deficient phenotypes in an European population study. Naunyn Schmiedebergs Arch Pharmacol 321: 33Google Scholar
  45. Kupfer A, Desmond P, Patwardhan R, Schenker S, Branch RA (1984) Mephenytoin hydroxylation deficiency: kinetics after repeated doses. Clin Pharmacol Ther 35: 33–39PubMedCrossRefGoogle Scholar
  46. Larrey D, Distelrath LM, Dannan GA, Wilkinson G, Guengerich FP (1984) Purification and characterisation of the rat liver microsomal cytochrome P450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism. Biochemistry 23: 2787–2795PubMedCrossRefGoogle Scholar
  47. Lou YC (1990) Differences in drug metabolism polymorphism between orientals and Caucasians. Drug Metab Rev 22: 451–475PubMedCrossRefGoogle Scholar
  48. Mahgoub A, Idle JR, Smith RL (1979) A population and familial study of the defective alicyclic hydroxylation of debrisoquine among Egyptians. Xenobiotica 9: 51–56PubMedCrossRefGoogle Scholar
  49. Matsunaga E, Zanger UM, Hardwick JP, Gelboin HV, Meyer UA, Gonzalez FJ (1989) The CYP2D gene subfamily: analysis of the molecular basis of the debrisoquine 4-hydroxylase deficiency in DA rats. Biochemistry 28: 7349–7355PubMedCrossRefGoogle Scholar
  50. Matsunaga E, Umeno M, Gonzalez FJ (1990) The rat P450 IID subfamily: complete sequences of four closely linked genes and evidence that gene conversions maintained sequence homogeneity at the heme-binding region of the cytochrome P450 active site. J Mol Evol 30: 155–169PubMedCrossRefGoogle Scholar
  51. Mbanefo C, Bababunmi EA, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A study of the debrisoquine hydroxylation polymorphism in a Nigerian population. Xenobiotica 10: 811–818PubMedCrossRefGoogle Scholar
  52. Meehan RR, Gosden JR, Rout D, Hastie ND, Friedberg T, Adesnik M, Buckland R, van Heyningen V, Fletcher J, Spurr NK, Sweeney J, Wolf CR (1988) Human cytochrome P450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Hum Genet 42: 26–37PubMedGoogle Scholar
  53. Meier UT, Meyer UA (1987) Genetic polymorphism of human cytochrome P450 (S′)-mephenytoin 4-hydroxylase. Studies with human autoantibodies suggest a functionally altered cytochrome P450 isozyme as cause of the genetic deficiency. Biochemistry 26: 8466–8474PubMedCrossRefGoogle Scholar
  54. Miners JO, Wing LMH, Birkett DJ (1985) Normal metabolism of debrisoquine and theophylline in a slow tolbutamide metaboliser. Aust NZ J Med 15: 348–349CrossRefGoogle Scholar
  55. Mura C, Broyard JP, Jacqz-Aigrain E, Krishnamoorthy R (1991) Distinct phenotypes and genotypes of debrisoquine hydroxylation among Europeans and Chinese. Br J Clin Pharmacol 32: 135–136PubMedGoogle Scholar
  56. Oates NS, Shah RR, Idle JR, Smith RL (1982) Genetic polymorphism of phenformin 4-hydroxylation. Clin Pharmacol Ther 32: 81–89PubMedCrossRefGoogle Scholar
  57. Penno MB, Vesell ES (1983) Monogenic control of variations in antipyrine metabolite formation. J Clin Invest 71: 1698–1709PubMedCrossRefGoogle Scholar
  58. 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 an RFLP. Am J Hum Genet 48: 720–725PubMedGoogle Scholar
  59. 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
  60. Renwick AG, Robertson DRC, Macklin B, Challenor V, Waller DG, George CF (1988) The pharmacokinetics of nifedipine — a population study. Br J Clin Pharmacol 25: 701–708PubMedGoogle Scholar
  61. 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
  62. Roots L, Drakoulis N, Ploch M, Heinemeyer G, Loddenkemper R, Minks T, Nitz M, Otte F, Koch M (1988) Debrisoquine hydroxylation phenotype, acetylation phenotype and ABO blood groups as genetic host factors of lung cancer risk. Klin Wochenschr 66 [Suppl XI]: 87–97PubMedCrossRefGoogle Scholar
  63. Schellens JHM, Soons PA, Breimer DD (1988) Lack of bimodality in nifedipine plasma kinetics in a large population of healthy subjects. Biochem Pharmacol 37: 2507–2510PubMedCrossRefGoogle Scholar
  64. Scott J, Poffenbarger PL (1979) Pharmacogenetics of tolbutamide metabolism in humans. Diabetes 28: 41–51PubMedCrossRefGoogle Scholar
  65. Shimada T, Misono KS, Guengerich FP (1986) Human liver microsomal cytochrome P450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism. J Biol Chem 261: 900–921Google Scholar
  66. Skoda RC, Gonzalez FJ, Demierre A, Meyer UA (1988) Two mutant alleles of the human cytochrome P450dbl gene (P450C2D1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci USA 85: 5240–5243PubMedCrossRefGoogle Scholar
  67. Speirs CJ, Murray S, Davies DS, Biola Mabadeje AF, Boobis AR (1990) Debrisoquine oxidation phenotype and susceptibility to lung cancer. Br J Clin Pharmacol 29: 101–109PubMedGoogle Scholar
  68. Sugimura H, Caporaso NE, Shaw GL, Modali RV, Gonzalez FJ, Hoover RN, Resau JH, Trump BF, Weston A, Harris CC (1990) Human debrisoquine hydroxylase gene polymorphisms in cancer patients and controls. Carcinogenesis 11: 1527–1530PubMedCrossRefGoogle Scholar
  69. Tefre T, Ryberg D, Haugen A, Nebert DW, Skaug V, Brogger A, Borresen A-L (1991) Lack of association between an Mspl polymorphism in the CYPIA1 gene (P450IA1) and increased risk of lung cancer in a Norwegian population. Pharmacogenetics 1: 20–25PubMedCrossRefGoogle Scholar
  70. Tyndale R, Aoyama T, Broly F, Matsunaga T, Inaba T, Kalow W, Gelboin HV, Meyer UA, Gonzalez FJ (1991) Identification of a new variant CYP2D6 allele associated with deficient in vitro metabolism of sparteine and bufuralol. Pharmacogenetics 1: 26–32PubMedCrossRefGoogle Scholar
  71. Uemsatsu F, Kikuchi H, Motomiya M, Abe T, Sagami I, Ohmachi T, Wakui A, Kanamaru R, Watanabe M (1991) Association between restriction fragment polymorphism of the human P450IIE1 gene and susceptibility to lung cancer. Jpn J Cancer Res 82: 254–256CrossRefGoogle Scholar
  72. Umbenhauer DR, Martin MV, Lloyd RS, Guengerich FP (1987) Cloning and sequence determination of a complementary DNA related to human liver microsomal cytochrome P450 S-mephenytoin 4-hydroxylase. Biochemistry 26: 1094–1099PubMedCrossRefGoogle Scholar
  73. Veronese ME, Mackenzie PI, Doecke CJ, McManus ME, Miners JO, Birkett DJ (1991) Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9. Biochem Biophys Res Commun 175: 1112–1118PubMedCrossRefGoogle Scholar
  74. Vincent-Viry M, Deshayes S, Mothe O, Siest G, Galteau MM (1988) Hydroxylation of debrisoquine using perfused liver isolated from Sprague-Dawley and DA rats: comparison with in vivo results. J Pharm Pharmacol 40: 694–670CrossRefGoogle Scholar
  75. Yamano S, Tatsuno J, Gonzalez FJ (1990) The CYP2A3 gene product catalyses coumarin 7-hydroxylation in human liver microsomes. Biochemistry 29: 1322–1329PubMedCrossRefGoogle Scholar
  76. 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: 493–501Google Scholar
  77. Yasumori T, Murayama N, Yamazoe Y, Abe A, Nogi Y, Fukasawa T, Kato R (1989) Expression of a human P-450IIC gene in yeast cells using galactose-inducible expression system. Mol Pharmacol 35: 443–449PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • A. K. Daly
  • J. R. Idle

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