Clinical Pharmacokinetics

, Volume 26, Issue 1, pp 59–70 | Cite as

Pharmacogenetic Phenotyping and Genotyping

Present Status and Future Potential
  • Frank J. Gonzalez
  • Jeffrey R. Idle
Review Article Clinical Pharmacokinetic Concepts

Summary

Enzymes that metabolise foreign compounds exhibit a large degree of interindividual variability in their levels of expression. In a number of instances this variability can be accounted for by null or variant alleles resulting from mutations in genes encoding these enzymes. Human variability in drug metabolism can be determined by biochemical and pharmacological assays. In cases where a genetic change has been characterised, polymerase chain reaction techniques have been developed to diagnose metabolism deficiencies.

Genetic differences in certain foreign compound metabolising enzymes such as glutathione S-transferase M1, N-acetyltranferase 2 and CYP2D6 have been shown to be associated with risk for developing environmentally and occupationally based diseases such as cancer. Drug therapy can also be compromised by the existence of genetic deficiencies in a number of enzymes, including CYP2D6. It is anticipated that determination of an individual’s drug metabolism capabilities by use of phenotyping and genotyping tests will allow for more rational and safe drug administration protocols.

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References

  1. Agarwal DP, Goedde HW. Pharmacogenetics of alcohol metabolism and alcholism. Pharmacogenetics 2: 48–62, 1992PubMedCrossRefGoogle Scholar
  2. Andersson T, Regårdh CG, Dahl-Puustinen ML, Bertilsson L. Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Therapeutic Drug Monitoring 12: 415–416, 1990PubMedCrossRefGoogle Scholar
  3. Aoyama T, Yamano S, Waxman DJ, Meyer UA, Fisher V, et al. Cytochrome P450 hPCN3, a novel P450 III? gene product that is differentially expressed in adult human liver: cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. Journal of Biological Chemistry 264: 10388–10395, 1989PubMedGoogle Scholar
  4. Atkins S, Gan KN, Mody M, La Du BN. Molecular basis for the polymorphic forms of serum paraoxonase/arylesterase: glutamine or arginine at position 191, for respective A or B allozymes. American Journal of Human Genetics 52: 598–608, 1993Google Scholar
  5. Bell DA, Taylor JA, Paulson DF, Robertson CN, Mohler JL, et al. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. Journal of the National Cancer Institute 85: 1159–1164, 1993PubMedCrossRefGoogle Scholar
  6. Blum M, DeMierre A, Grant DM, Heim M, Meyer UA. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proceedings of the National Academy of Sciences of the United States of America 88: 5237–5241, 1991PubMedCrossRefGoogle Scholar
  7. Boddy AV, Furtun Y, Sardas S, Sardas O, Idle JR. Interindividual variation in the activation and inactivation metabolic pathways of cyclophosphamide. Journal of the National Cancer Institute 84: 1744–1748, 1992PubMedCrossRefGoogle Scholar
  8. Broly F, Gaedigk A, Heim M, Eichelbaum M, Morike K, et al. Debrisoquine/spartein hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA and Cell Biology 10: 545–558, 1991PubMedCrossRefGoogle Scholar
  9. Buchert E, Woosley RL. Clinical implications of variable antiarrythmic drug metabolism. Pharmacogenetics 2: 2–11, 1992PubMedCrossRefGoogle Scholar
  10. Butler MA, Lang NP, Young JF, Caporaso NE, Vineas P, et al. Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics 2: 116–127, 1992PubMedCrossRefGoogle Scholar
  11. Caporaso N, Landi MT, Vineis P. Relevance of metabolic polymorphisms to human carcinogenesis: evaluation of epidemiologic evidence. Pharmacogenetics 1: 4019, 1991CrossRefGoogle Scholar
  12. Cholerton S, Idle ME, Vas A, Gonzalez FJ, Idle JR. Comparison of a novel thin-layer chromatography-fluorescence detection method with a spectrofluorometric method for the determination of 7-hydroxycoumarin in human urine. Journal of Chromatography 575: 325–330, 1992PubMedCrossRefGoogle Scholar
  13. Cholerton S, Smith RL. Human pharmacogenetics of nitrogen oxidations. In Hlavica & Damani (Eds) N-oxidation of drugs: biochemistry, pharmacology, toxicology, pp. 107–131, Chapman & Hall, London, 1991Google Scholar
  14. Dahl ML, Bertilsson L. Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics 3: 61–70, 1993PubMedCrossRefGoogle Scholar
  15. Daly AK, Armstrong M, Monkman SC, Idle ME, Idle JR. Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenoytpes. Pharmacogenetics 1: 33–41, 1991PubMedCrossRefGoogle Scholar
  16. Daly AK, Salh BS, Bilton D, Allen J, Knight AD, et al. Deficient nifedipine oxidation: a rare inherited trait associated with cystic fibrosis kindreds. Pharmacogenetics 2: 19–24, 1992PubMedCrossRefGoogle Scholar
  17. Daly AK, Thomas DJ, Cooper J, Pearson WR, Neal DE, et al. Homozygous deletion of the glutathione S-transferase M1 (GSTM1) gene is a risk factor in bladder cancer. British Medical Journal 307: 481–482, 1993PubMedCrossRefGoogle Scholar
  18. Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dehydropyrimidine dehydrogenase biochemical basis for familial pyrimidemia and seven 5-fluorouracil-induced toxicity. Journal of Clinical Investigation 81: 47–51, 1988PubMedCrossRefGoogle Scholar
  19. Eichelbaum M, Gross AS. The genetic polymorphism of debrisoquine/sparteine metabolism-clinical aspects. Pharmacology and Therapeutics 46: 377–394, 1990PubMedCrossRefGoogle Scholar
  20. Evans WE, Relling MV. Concordance of P450 2D6 (debrisoquine hydroxylase) phenotype and genotype: inability of dextromethorphan metabolic ratio to descriminate reliably heterozygous and homozygous extensive metabolizers. Pharmacogenetics 1: 143–148, 1991PubMedCrossRefGoogle Scholar
  21. Gonzalez FJ, Meyer UA. Molecular genetics of the debrisoquine/sparteine polymorphism. Clinical Pharmacology and Therapeutics 50: 233–238, 1991PubMedCrossRefGoogle Scholar
  22. Gonzalez FJ, Nebert DW. Evolution of the P450 gene superfamily: animal-plant ‘warfare’, molecular drive and human genetic differences in drug oxidation. Trends in Genetics 6: 182–187, 1990PubMedCrossRefGoogle Scholar
  23. Grant DM. Molecular genetics of the N-acetyltransferases. Pharmacogenetics 3: 45–50, 1993PubMedCrossRefGoogle Scholar
  24. Guengerich FP. Mechanism-based inactivation of human liver cytochrome P450 IIIA4 by gestadene. Chemical Research in Toxicology 3: 363–371, 1990PubMedCrossRefGoogle Scholar
  25. Guengerich FP, Kim DH, Iwasaki M. Role of human cytochrome P450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chemical Research in Toxicology 4: 158–178, 1991Google Scholar
  26. Hadadi AFA, Coulter CEA, Idle JR. Phenotypical deficient urinary elimination of carboxyphosphamide after cyclophosphamide administration to cancer patients. Cancer Research 48: 5167–5171, 1988Google Scholar
  27. Hajra A, Sorenson RC, La Du BN. Detection of human DNA mutations with nonradioactive allele-specific oligonucleotide probes. Pharmacogenetics 2: 78–88, 1992PubMedCrossRefGoogle Scholar
  28. Hall MCS, Gregory WL, Idle JR. Pharmacogenetics: can the therapeutic key objective be accomplished. In Weatman & Seymour (Eds) Horizons in medicine, McGraw-Hill, London, in press, 1994Google Scholar
  29. Hassett C, Richter RJ, Humbert R, Chapline C, Crabb JW, et al. Characterization of cDNA clones encoding rabbit and human serum paraoxonase: the mature protein retains its signal sequence. Biochemistry 30: 10141–10149, 1991PubMedCrossRefGoogle Scholar
  30. Hickman D, Sim E. N-Acetyltransferase polymorphism: comparison of phenotype and genotype in humans. Biochemical Pharmacology 42: 1007–1014, 1991PubMedCrossRefGoogle Scholar
  31. Honchel R, Aksoy IA, Szumanski C, Wood TC, Otterness DM, et al. Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. Molecular Pharmacology 43: 878–887, 1993PubMedGoogle Scholar
  32. Hunt CM, Watkins PB, Saenger P, Stave GM, Barlascini N, et al. Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clinical Pharmacology and Therapeutics 51: 18–23, 1992PubMedCrossRefGoogle Scholar
  33. Idle JR, Armstrong M, Boddy AV, Boustead C, Cholerton S, et al. The pharmacogenetics of chemical carcinogenesis. Pharmacogenetics 2: 246–258, 1992PubMedCrossRefGoogle Scholar
  34. Kalow W. Pharmacogenetics: heredity and the response to drugs, W.B. Saunders, Philadelphia, 1962Google Scholar
  35. Kleinbloesem CH, van Brummelen P, Faber H, Danhof M, Vermeulen NP, et al. Variability in nifedipine kinetics and dynamics: a new oxidation polymorphism in man. Biochemical Pharmacology 33: 3721–3724, 1984PubMedCrossRefGoogle Scholar
  36. La Du BN. Human serum paraoxonase/arylesterase. In Kalow (Ed.) Pharmacogenetics of drug metabolism, pp. 51–91, Pergamon Press Inc., New York, 1992Google Scholar
  37. Lawton MP, Philpot RM. Molecular genetics of the flavin-dependent monooxygenases. Pharmacogenetics 3: 40–44, 1993PubMedCrossRefGoogle Scholar
  38. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336: 225–229, 1990PubMedCrossRefGoogle Scholar
  39. Lennard L, van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathroprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clinical Pharmacology and Therapeutics 46: 149–154, 1989PubMedCrossRefGoogle Scholar
  40. Lennard MS, Lewis RV, Brown LA, Tucker GT, Ramsay LE, et al. Timolol metabolism and debrisoquine hydroxylation polymorphism: a population study. British Journal of Clinical Pharmacology 27: 429–434, 1989PubMedCrossRefGoogle Scholar
  41. Lucey MR, Kolars JC, Merion RM, Campbell DA, Aldrich M, et al. Cyclosporin toxicity at therapeutic blood levels and cytochrome P450 III?. Lancet 335: 11–15, 1990PubMedCrossRefGoogle Scholar
  42. Motulsky AG. Drug reactions, enzymes and biochemical genetics. Journal of the American Medical Association 165: 835–837, 1957PubMedCrossRefGoogle Scholar
  43. Nelson DR, Kamataki T, Waxman DL, Guengerich FP, Estabrook RW, et al. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA and Cell Biology 12: 1–51, 1993PubMedCrossRefGoogle Scholar
  44. Owens IS, Ritter JK. The novel bilirubin/phenol UDP-glucuronosyltransferase UGT1 locus: implications for multiple nonhemolytic familial hyperbelirubinemia phenotypes. Pharmacogenetics 2: 93–108, 1992PubMedCrossRefGoogle Scholar
  45. Patel M, Tang BK, Kalow W. Variability of acetaminophen metabolism in Caucasians and Orientals. Pharmacogenetics 2: 38–45, 1992PubMedCrossRefGoogle Scholar
  46. Peter R, Bocker R, Beaune PH, Iwasaki M, Guengerich FP, et al. Hydroxylation of chlorzoxasone as a specific probe for human liver cytochrome P450 IIE1. Chemical Research in Toxicology 3: 566–573, 1990PubMedCrossRefGoogle Scholar
  47. Price RA, Cox NJ, Spielman RS, Van Loon JA, Maidak BL, et al. Inheritance of human platelet thermolabile phenol sulphotransferase (TL PST) activity. Genetic Epidemiology 5: 1–15, 1988PubMedCrossRefGoogle Scholar
  48. Price RA, Spielman RS, Lucena AL, Van Loon JA, Maidak BL, et al. Genetic polymorphism for human platelet thermostable phenol sulphotransferase (TS PST) activity. Genetics 122: 905–914, 1989PubMedGoogle Scholar
  49. Relling MV, Aoyama T, Gonzalez FJ, Meyer UA. Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP26 subfamily. Journal of Pharmacology and Experimental Therapeutics 252: 442–447, 1990PubMedGoogle Scholar
  50. Rettie AE, Korzekwa KK, Kunze KL, Lawrence RF, Eddyll AC, et al. Hydroxylation of warfarin by human liver cytochrome P450: a role for proteins encoded by CYP2C9 in etiology of anticoagulation drug interactions. Chemical Research in Toxicology 5: 54–59, 1992PubMedCrossRefGoogle Scholar
  51. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Deficient (S)-warfarin metabolism catalyzed by the R144C allelic variant of CYP2C9. Pharmacogenetics, in press, 1994Google Scholar
  52. Ritter JK, Yeatman MT, Ferreira P, Owens IS. Identification of a genetic alteration in the code for bilirubin UDP-glucuronosyltransferase in the UDP gene complex of a Crigler-Najjar type I patient. Journal of Clinical Investigation 90: 150–155, 1992PubMedCrossRefGoogle Scholar
  53. Rost KL, Brosicke H, Brockmoller J, Scheffler M, Helge H, et al. Increase of cytochrome P450IA2 activity by omeprazole: evidence by the 13C-[N-3-methyl]-caffeine breath test in poor and extensive metabolizers of S-mephenytoin. Clinical Pharmacology and Therapeutics 52: 170–180, 1992PubMedCrossRefGoogle Scholar
  54. Rothman N, Hayes RB, Bi W, Caporaso N, Broly F, et al. Correlation between N-acetyltranserase activity and NAT2 genotype in Chinese males. Pharmacogenetics 3: 250–255, 1993PubMedCrossRefGoogle Scholar
  55. Seidergard J, Vorachek WR, Pero RW, Pearson WR. Hereditary differences in the expression of the human glutathione S-transferase active on trans-stilbene oxide are due to gene deletion. Proceedings of the National Academy of Sciences of the United States of America 45: 7293–7297, 1988CrossRefGoogle Scholar
  56. Tang BK, Kadar D, Kalow W. An alternative test for acetylator phenotyping with caffeine. Clinical Pharmacology and Therapeutics 42: 509–513, 1987PubMedCrossRefGoogle Scholar
  57. Tuchman M, Stoeckeler JS, Kiang DT, O’Dea RF, Ramnaraine ML, et al. Familial pyrimidemia and pyrimidinuria associated with severe fluorouracil toxicity. New England Journal of Medicine 313: 245–249, 1985PubMedCrossRefGoogle Scholar
  58. Tyndale R, Aoyama T, Broly F, Matsunaga T, Inaba T, et al. Identification of a new CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabplizer (cytochrome P4502D6) phenotypes. Pharmacogenetics 1: 26–31, 1991PubMedCrossRefGoogle Scholar
  59. Watkins PB, Murray SA, Winkelman LG, Heuman DM, Wrighton SA, et al. Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochrome P450. Journal of Clinical Investigation 83: 688–697, 1989PubMedCrossRefGoogle Scholar
  60. Weber WW. The acetylator genes and drug response, Oxford University Press, New York, 1987Google Scholar
  61. Weber WW, Vatsis KP. Individual variability in p-aminobenzoic acid N-acetylation by human N-acetyltransferase (NAT1) of peripheral blood. Pharmacogenetics 3: 209–212, 1993PubMedCrossRefGoogle Scholar
  62. Weinshilboum R. Methyltransferase pharmacogenetics. Pharmacology and Therapeutics 43: 77–90, 1989PubMedCrossRefGoogle Scholar
  63. Whittaker M. Cholinesterase, Karger, Basel, 1986Google Scholar
  64. Wilkinson G, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. In Kalow (Ed.) Pharmacogenetics of drug metabolism, pp. 657–685, Pergamon Press Inc., New York, 1992Google Scholar
  65. Woolhouse N, Adjepon-Yamoah KK, Mellström B, Hedman A, Bertillson L, et al. Nortriptyline and debrisoquine hydroxylations in Ghanaian and Swedish subjects. Clinical Pharmacology and Therapeutics 36: 374–378, 1984PubMedCrossRefGoogle Scholar
  66. Yamazoe Y, Nagata K. Genetic polymorphism in human drug metabolism. Nippon Yakurigaku Zasshi 101: 69–77, 1993PubMedCrossRefGoogle Scholar
  67. Yokota H, Tamura S, Furuya H, Kimura S, Watanabe M, et al. Evidence for a new variant CYP2D6 allele, CYP2D6J, in a Japanese population associated with lower in vivo rates of sparteine metabolism. Pharmacogenetics 3: 256–263, 1993PubMedCrossRefGoogle Scholar
  68. Yoshida A. Molecular genetics of human aldehyde dehydrogenase. Pharmacogenetics 2: 139–147, 1992PubMedCrossRefGoogle Scholar
  69. Yue QY, Svensson JO, Alm C, Sjöqvist F, Säwe J. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. British Journal of Clinical Pharmacology 28: 539–545, 1989Google Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Frank J. Gonzalez
    • 1
    • 2
    • 3
  • Jeffrey R. Idle
    • 1
    • 2
    • 3
  1. 1.Laboratory of Molecular Carcinogenesis, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Pharmacogenetics Unit, Department of Pharmacological Sciences, Medical SchoolUniversity of Newcastle upon TyneNewcastle upon TyneEngland
  3. 3.GenoType LtdJesmond, Newcastle upon TyneEngland

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