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Genetic Polymorphisms and Cardiovascular Drug Metabolism

  • Chapter
Book cover Cardiovascular Pharmacogenetics

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 160))

Abstract

Both the therapeutic and the adverse effects of drugs can be profoundly influenced by the activity of enzymes of drug metabolism. Biotransformation is effected by a number of families of structurally and functionally related enzymes, which inactivate and ultimately enable the excretion of therapeutic agents. The enzymes of drug metabolism exhibit broad and overlapping substrate specificities. Many of these enzymes are now known to exhibit polymorphic expression, due often to point mutations in the structural gene. The result may be a large difference in metabolic activity, and consequently in the pharmacokinetics, between phenotypes. Examples of polymorphic enzymes include CYP2D6, CYP2C9, CYP2C19 and NAT2. Some drug transporters such as ABCB1 (P-glycoprotein) are also polymorphic. The consequences of such polymorphism will depend upon a number of factors, including the steepness of the concentration-effect curve, the contribution of the polymorphic pathway to overall elimination and the magnitude of other sources of variability in the effect of the polymorphic enzyme. In this last case, whilst it might be possible to demonstrate clear differences in effect between phenotypes in healthy volunteers, other sources of variability, including the disease itself, may dominate differences in response in patients. There are some clear examples of the importance of polymorphic drug metabolism in the effects of drugs, such as CYP2C9 and warfarin and NAT2 and hydralazine. However, it is likely that the extent to which genotyping might benefit the individual patient will be established only in adequate clinical studies.

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References

  • Aklillu E, Persson I, Bertilsson L et al (1996) Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 278: 441–446

    PubMed  CAS  Google Scholar 

  • Aklillu E, Herrlin K, Gustafsson LL et al (2002) Evidence for environmental influence on CYP2D6-catalysed debrisoquine hydroxylation as demonstrated by phenotyping and genotyping of Ethiopians living in Ethiopia or in Sweden. Pharmacogenetics 12: 375–383

    Google Scholar 

  • Ameyaw MM, Regateiro F, Li T et al (2001) MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 11: 217–221

    Article  PubMed  CAS  Google Scholar 

  • Armstrong M, Fairbrother K, Idle JR et al (1994) The cytochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population. Pharmacogenetics 4: 73–81

    Article  PubMed  CAS  Google Scholar 

  • Ashmarin IP, Danilova RA, Obukhova MF et al (2000) Main ethanol metabolizing alcohol dehydrogenases (ADH I and ADH IV): biochemical functions and the physiological manifestation. FEBS Lett 486: 49–51

    Article  PubMed  CAS  Google Scholar 

  • Bathum L, Skjelbo E, Mutabingwa TK et al (1999) Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population. Br J Clin Pharmacol 48: 395–401

    Article  PubMed  CAS  Google Scholar 

  • Bertilsson L, Lou YQ, Du YL et al (1992) Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 51: 388–397

    Article  PubMed  CAS  Google Scholar 

  • Binda C, Mattevi A and Edmondson DE (2002) Structure-function relationships in flavoenzyme-dependent amine oxidations: a comparison of polyamine oxidase and monoamine oxidase. J Biol Chem 277: 23973–23976

    Article  PubMed  CAS  Google Scholar 

  • Borst P, Evers R, Kool M et al (2000) A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 92: 1295–1302

    Article  PubMed  CAS  Google Scholar 

  • Cashman JR and Zhang J (2002) Interindividual differences of human flavin-containing monooxygenase 3: genetic polymorphisms and functional variation. Drug Metab Dispos 30: 1043–1052

    Article  PubMed  CAS  Google Scholar 

  • Cesura AM and Pletscher A (1992) The new generation of monoamine oxidase inhibitors. Prog Drug Res 38: 171–297

    PubMed  CAS  Google Scholar 

  • Coughtrie MW and Johnston LE (2001) Interactions between dietary chemicals and human sulfotransferases-molecular mechanisms and clinical significance. Drug Metab Dispos 29: 522–528

    PubMed  CAS  Google Scholar 

  • Dahl ML, Johansson I, Bertilsson L et al (1995) Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther 274: 516–520

    Google Scholar 

  • Daly AK (1995) Molecular basis of polymorphic drug metabolism. J Mol Med 73: 539–553

    Google Scholar 

  • De Morais SM, Wilkinson GR, Blaisdell J et al (1994) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269: 15419–15422

    Google Scholar 

  • Dickmann LJ, Rettie AE, Kneller MB et al (2001) Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 60: 382–387

    PubMed  CAS  Google Scholar 

  • Droll K, Bruce-Mensah K, Otton SV et al (1998) Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians. Pharmacogenetics 8: 325–333

    Google Scholar 

  • Eichelbaum M and Gross AS (1990) The genetic polymorphism of debrisoquine/sparteine metabolism-clinical aspects. Pharmacol Ther 46: 377–394

    Article  PubMed  CAS  Google Scholar 

  • Eichelbaum M, Kroemer HK and Fromm MF (1997) Impact of P450 genetic polymorphism on the first-pass extraction of cardiovascular and neuroactive drugs. Adv Drug Deliv Rev 27: 171–199

    Article  PubMed  Google Scholar 

  • Evans DA (1993) Methylation reactions. In ‘Genetic factors in drug therapy: Clinical and molecular pharmacogenetics’. Cambridge University Press, New York. pp. 330–345

    Google Scholar 

  • Fernandez-Salguero P, Hoffman SM, Cholerton S et al (1995) A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am J Hum Genet 57: 651–660

    PubMed  CAS  Google Scholar 

  • Foliot A, Touchard D and Celier C (1984) Impairment of hepatic glutathione S-transferase activity as a cause of reduced biliary sulfobromophthalein excretion in clofibratetreated rats. Biochem Pharmacol 33: 2829–2834

    Article  PubMed  CAS  Google Scholar 

  • Fretland AJ and Omiecinski CJ (2000) Epoxide hydrolases: biochemistry and molecular biology. Chem Biol Interact 129: 41–59

    Article  PubMed  CAS  Google Scholar 

  • Friedgen B, Wolfel R, Russ H et al (1996) The role of extraneuronal amine transport systems for the removal of extracellular catecholamines in the rabbit. Naunyn Schmiedebergs Arch Pharmacol 354: 275–286

    Article  PubMed  CAS  Google Scholar 

  • Frye RF and Branch RA (2002) Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects. Br J Clin Pharmacol 53: 155–162

    Article  PubMed  CAS  Google Scholar 

  • Fuhr U, Woodcock BG and Siewert M (1992) Verapamil and drug metabolism by the cytochrome P450 isoform CYP1A2. Eur J Clin Pharmacol 42: 463–464

    PubMed  CAS  Google Scholar 

  • Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294: 1871–1875

    Article  PubMed  CAS  Google Scholar 

  • Fumes B, Feng J, Sommer SS et al (2003) Identification of novel variants of the flavincontaining monooxygenase gene family in African Americans. Drug Metab Dispos 31: 187–193

    Article  Google Scholar 

  • Gaedigk A, Blum M, Gaedigk R et al (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: 943–950

    PubMed  CAS  Google Scholar 

  • Garrod AE (1914) Medicine from the Chemical Standpoint. Lancet ii: 281–289

    Google Scholar 

  • Glatt H, Boeing H, Engelke CE et al (2001) Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects. Mutat Res 482: 27–40

    Article  PubMed  CAS  Google Scholar 

  • Goedde HW, Agarwal DP, Fritze G et al (1992) Distribution of ADH2 and ALDH2 genotypes in different populations. Hum Genet 88: 344–346

    Article  PubMed  CAS  Google Scholar 

  • Goldstein JA and De Morais SM (1994) Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4: 285–299

    Article  PubMed  CAS  Google Scholar 

  • Goldstein JA, Ishizaki T, Chiba K et al (1997) Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 7: 5964

    Google Scholar 

  • Grancharov K, Naydenova Z, Lozeva S et al (2001) Natural and synthetic inhibitors of UDP-glucuronosyltransferase. Pharmacol Ther 89: 171–186

    Article  PubMed  CAS  Google Scholar 

  • Grant DM, Goodfellow GH, Sugamori K et al (2000) Pharmacogenetics of the human arylamine N-acetyltransferases. Pharmacology 61: 204–211

    Article  PubMed  CAS  Google Scholar 

  • Haining RL, Hunter AP, Veronese ME et al (1996) Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 333: 447–458

    Article  PubMed  CAS  Google Scholar 

  • Hayes JD and Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30: 445–600

    Article  PubMed  CAS  Google Scholar 

  • Hayes JD and Strange RC (2000) Glutathione S-transferase polymorphisme and their biological consequences. Pharmacology 61: 154–166

    Article  PubMed  CAS  Google Scholar 

  • Hein DW (2002) Molecular genetics and function of NATI and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res 506–507: 65–77

    Google Scholar 

  • Herrlin K, Massele AY, Jande M et al (1998) Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. Clin Pharmacol Ther 64: 391–401

    Article  PubMed  CAS  Google Scholar 

  • Hines RN and McCarver DG (2002) The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther 300: 355–360

    Article  PubMed  CAS  Google Scholar 

  • Hoffmeyer S, Burk O, von Richter O et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97: 3473–3478

    Google Scholar 

  • Hollenberg PF (2002) Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes. Drug Metab Rev 34: 17–35

    Article  PubMed  CAS  Google Scholar 

  • Holmes RS (1994) Alcohol dehydrogenases: a family of isozymes with differential functions. Alcohol Alcohol Suppl 2: 127–130

    PubMed  CAS  Google Scholar 

  • Hustert E, Haberl M, Burk O et al (2001) The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11: 773–779

    Article  PubMed  CAS  Google Scholar 

  • Ingelman-Sundberg M (2001) Genetic variability in susceptibility and response to toxicants. Toxicol Lett 120: 259–268

    Article  PubMed  CAS  Google Scholar 

  • Irshaid YM, Gharaybeh KI, Ammari FF et al (1990) Glucuronidation of 7-hydroxy-4methylcoumarin by human liver microsomes. Inhibition by certain drugs. Eur J Drug Metab Pharmacokinet 15: 295–301

    Google Scholar 

  • Johansson I, Lundqvist E, Bertilsson L et al (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci U S A 90: 11825–11829

    Article  PubMed  CAS  Google Scholar 

  • Jornvall H, Hoog JO, Persson B et al (2000) Pharmacogenetics of the alcohol dehydrogenase system. Pharmacology 61: 184–191

    Article  PubMed  CAS  Google Scholar 

  • Kagimoto M, Heim M, Kagimoto K et al (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: 17209–17214

    Google Scholar 

  • Kazierad DJ, Martin DE, Blum RA et al (1997) Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers. Clin Pharmacol Ther 62: 417–425

    Article  PubMed  CAS  Google Scholar 

  • Krueger SK, Martin SR, Yueh MF et al (2002) Identification of active flavin-containing monooxygenase isoform 2 in human lung and characterization of expressed protein. Drug Metab Dispos 30: 34–41

    Article  PubMed  CAS  Google Scholar 

  • Krynetski EY, Tai HL, Yates CR et al (1996) Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6: 279–290

    Article  PubMed  CAS  Google Scholar 

  • Kuehl P, Zhang J, Lin Y et al (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27: 383–391

    Google Scholar 

  • Kupfer A and Preisig R (1984) Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 26: 753–759

    Article  PubMed  CAS  Google Scholar 

  • Kutt H, Wolk M, Scherman R and McDowell F (1964) Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity. Neurology 14: 542–548

    Article  PubMed  CAS  Google Scholar 

  • Lachman HM, Papolos DF, Saito T et al (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6: 243–250

    Article  PubMed  CAS  Google Scholar 

  • Lennard L (1998) Clinical implications of thiopurine methyltransferase-optimization of drug dosage and potential drug interactions. Ther Drug Monit 20:527–531

    Google Scholar 

  • Lieber CS (1997) Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev 77: 517–544

    Google Scholar 

  • Liu C, Zhuo X, Gonzalez FJ et al (1996) Baculovirus-mediated expression and characterization of rat CYP2A3 and human CYP2A6: role in metabolic activation of nasal toxicants. Mol Pharmacol 50: 781–788

    PubMed  CAS  Google Scholar 

  • Mahgoub A, Idle JR and Smith RL (1979) A population and familial study of the defective alicyclic hydroxylation of debrisoquine among Egyptians. Xenobiotica 9: 51–56

    Article  PubMed  CAS  Google Scholar 

  • Mannisto PT and Kaakkola S (1999) Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51: 593–628

    PubMed  CAS  Google Scholar 

  • Masimirembwa C, Hasler J, Bertilssons L et al (1996) Phenotype and genotype analysis of debrisoquine hydroxylase (CYP2D6) in a black Zimbabwean population. Reduced enzyme activity and evaluation of metabolic correlation of CYP2D6 probe drugs. Eur J Clin Pharmacol 51: 117–122

    Article  PubMed  CAS  Google Scholar 

  • Masimirembwa CM and Hasler JA (1997) Genetic polymorphism of drug metabolising enzymes in African populations: implications for the use of neuroleptics and antidepressants. Brain Res Bull 44: 561–571

    Article  PubMed  CAS  Google Scholar 

  • McGurk KA, Brierley CH and Burchell B (1998) Drug glucuronidation by human renal UDP-glucuronosyltransferases. Biochem Pharmacol 55: 1005–1012

    Article  PubMed  CAS  Google Scholar 

  • McLeod HL and Siva C (2002) The thiopurine S-methyltransferase gene locus—implications for clinical pharmacogenomics. Pharmacogenomics 3: 89–98

    Article  PubMed  CAS  Google Scholar 

  • Meister A (1995) Glutathione metabolism. Methods Enzymol 251: 3–7

    Article  PubMed  CAS  Google Scholar 

  • Meyer UA (1994) The molecular basis of genetic polymorphisms of drug metabolism. J Pharm Pharmacol 46 Suppl 1: 409–415

    Google Scholar 

  • Miners JO, McKinnon RA and Mackenzie PI (2002) Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance. Toxicology 181– 182:453–456

    Google Scholar 

  • Nebert DW and Russell DW (2002) Clinical importance of the cytochromes P450. Lancet 360: 1155–1162

    Google Scholar 

  • Ohyama K, Nakajima M, Suzuki M et al (2000) Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: prediction of in vivo drug interactions. Br J Clin Pharmacol 49: 244–253

    Article  PubMed  CAS  Google Scholar 

  • Oscarson M, Hidestrand M, Johansson I et al (1997) A combination of mutations in the CYP2D6*17 (CYP2D6Z) allele causes alterations in enzyme function. Mol Pharmacol 52: 1034–1040

    PubMed  CAS  Google Scholar 

  • Osier MV, Pakstis AJ, Soodyall H et al (2002) A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity. Am J Hum Genet 71: 84–99

    Article  PubMed  CAS  Google Scholar 

  • Pelkonen O and Raunio H (1997) Metabolic activation of toxins: tissue-specific expres- sion and metabolism in target organs. Environ Health Perspect 105 Suppl 4: 767–774

    Google Scholar 

  • Persson I, Aklillu E, Rodrigues F et al (1996) S-mephenytoin hydroxylation phenotype and CYP2C19 genotype among Ethiopians. Pharmacogenetics 6: 521–526

    Article  PubMed  CAS  Google Scholar 

  • Ploemen JH, van Ommen B and van Bladeren PJ (1990) Inhibition of rat and human glutathione S-transferase isoenzymes by ethacrynic acid and its glutathione conjugate. Biochem Pharmacol 40: 1631–1635

    Article  PubMed  CAS  Google Scholar 

  • Rettie AE, Wienkers LC, Gonzalez FJ et al (1994) Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 4: 39–42

    Article  PubMed  CAS  Google Scholar 

  • Rushmore TH and Kong AN (2002) Pharmacogenomics, regulation and signaling path- ways of phase I and II drug metabolizing enzymes. Curr Drug Metab 3: 481–490

    Article  PubMed  CAS  Google Scholar 

  • Schutz E, Gummert J, Mohr F et al (1993) Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 341:436-

    Google Scholar 

  • Scordo MG, Aklillu E, Yasar U et al (2001) Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 52: 447–450

    Article  PubMed  CAS  Google Scholar 

  • Scordo MG, Pengo V, Spina E et al (2002) Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 72: 702–710

    Article  PubMed  CAS  Google Scholar 

  • Shimada T, Yamazaki H, Mimura M et al (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270: 414–423

    PubMed  CAS  Google Scholar 

  • Simpson AE (1997) The cytochrome P450 4 (CYP4) family. Gen Pharmacol 28: 351–359

    Google Scholar 

  • Sohn DR, Shin SG, Park CW et al (1991) Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations. Br J Clin Pharmacol 32:504–507

    Google Scholar 

  • Steen VM, Molven A, Aarskog NK et al (1995) Homologous unequal cross-over involving a 2.8 kb direct repeat as a mechanism for the generation of allelic variants of human cytochrome P450 CYP2D6 gene. Hum Mol Genet 4: 2251–2257

    Article  PubMed  CAS  Google Scholar 

  • Streetman DS, Bertino JS Jr, Nafziger AN (2000) Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10: 187–216

    Article  PubMed  CAS  Google Scholar 

  • Sueyoshi T and Negishi M (2001) Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu Rev Pharmacol Toxicol 41: 123–143

    Article  PubMed  CAS  Google Scholar 

  • Sullivan-Klose TH, Ghanayem BI, Bell DA et al (1996) The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6: 341–349

    Article  PubMed  CAS  Google Scholar 

  • Taavitsainen P, Kiukaanniemi K and Pelkonen 0 (2000) In vitro inhibition screening of human hepatic P450 enzymes by five angiotensin-II receptor antagonists. Eur J Clin Pharmacol 56: 135–140

    Article  PubMed  CAS  Google Scholar 

  • Tai HL, Krynetski EY, Yates CR et al (1996) Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 58: 694–702

    PubMed  CAS  Google Scholar 

  • Tew KD and Ronai Z (1999) GST function in drug and stress response. Drug Resist Updat 2: 143–147

    Article  PubMed  CAS  Google Scholar 

  • Tracy TS, Korzekwa KR, Gonzalez FJ et al (1999) Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. Br J Clin Pharmacol 47: 545–552

    Article  PubMed  CAS  Google Scholar 

  • Treacy EP, Akerman BR, Chow LM et al (1998) Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet 7: 839–845

    Article  PubMed  CAS  Google Scholar 

  • Vasiliou V and Pappa A (2000) Polymorphisms of human aldehyde dehydrogenases. Consequences for drug metabolism and disease. Pharmacology 61: 192–198

    Article  PubMed  CAS  Google Scholar 

  • Vatsis KP, Weber WW, Bell DA et al (1995) Nomenclature for N-acetyltransferases. Pharmacogenetics 5: 1–17

    Article  PubMed  CAS  Google Scholar 

  • Wedlund PJ, Aslanian WS, McAllister CB et al (1984) Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 36: 773–780

    Article  PubMed  CAS  Google Scholar 

  • Weinshilboum R (2001) Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos 29: 601–605

    PubMed  CAS  Google Scholar 

  • Wilkinson GR, Guengerich FP and Branch RA (1989) Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 43: 53–76

    Article  PubMed  CAS  Google Scholar 

  • Xie HG, Kim RB, Stein CM et al (1999) Genetic polymorphism of (S)-mephenytoin 4’-hy- droxylation in populations of African descent. Br J Clin Pharmacol 48: 402–408

    Article  PubMed  CAS  Google Scholar 

  • Yamano S, Tatsuno J and Gonzalez FJ (1990) The CYP2A3 gene product catalyzes cou- marin 7-hydroxylation in human liver microsomes. Biochemistry 29: 1322–1329

    Article  PubMed  CAS  Google Scholar 

  • Yan M, Webster LT, Jr. and Blumer JL (2002) Kinetic interactions of dopamine and dobutamine with human catechol-O-methyltransferase and monoamine oxidase in vitro. J Pharmacol Exp Ther 301: 315–321

    Article  PubMed  CAS  Google Scholar 

  • Yasar U, Forslund-Bergengren C, Tybring G et al (2002) Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype. Clin Pharmacol Ther 71: 89–98

    Article  PubMed  CAS  Google Scholar 

  • Yeung CK, Lang DH, Thummel KE et al (2000) Immunoquantitation of FMO1 in human liver, kidney, and intestine. Drug Metab Dispos 28: 1107–1111

    PubMed  CAS  Google Scholar 

  • Yokota H, Tamura S, Furuya H et al (1993) 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

    Article  PubMed  CAS  Google Scholar 

  • Yoshida A, Huang IY and Ikawa M (1984) Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals. Proc Natl Acad Sci USA 81: 258–261

    Article  PubMed  CAS  Google Scholar 

  • Yun CH, Shimada T and Guengerich FP (1991) Purification and characterization of human liver microsomal cytochrome P-450 2A6. Mol Pharmacol 40: 679–685

    PubMed  CAS  Google Scholar 

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  1. Section on Clinical Pharmacology, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK

    A. R. Boobis, T. Shiga & R. J. Edwards

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  1. Experimental Medicine & Toxicology Imperial College London, Hammersmith Campus, Du Cane Road, W12 0NN, London, UK

    Martin R. Wilkins (Professor) (Professor)

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Boobis, A.R., Shiga, T., Edwards, R.J. (2004). Genetic Polymorphisms and Cardiovascular Drug Metabolism. In: Wilkins, M.R. (eds) Cardiovascular Pharmacogenetics. Handbook of Experimental Pharmacology, vol 160. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-06214-2_3

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