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Semin Vasc Med 2003; 03(3): 231-238
DOI: 10.1055/s-2003-44458
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Genetic Regulation of Warfarin Metabolism and Response

Ann K. Daly1 , Guruprasad P. Aithal2
  • 1Department of Pharmacological Sciences, University of Newcastle, Medical School, Newcastle upon Tyne, United Kingdom
  • 2Queen's Medical Centre University Hospital, Nottingham, United Kingdom
Further Information

Publication History

Publication Date:
21 November 2003 (online)

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ABSTRACT

Genetic factors make an important contribution to the wide interindividual variation in warfarin dose requirement. Several cytochromes P450, each of which shows genetic polymorphism leading to interindividual variation in levels of activity, contribute to oxidative metabolism of warfarin. The most important of these is CYP2C9, which 7-hydroxylates S-warfarin. In clinical studies, possession of the CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, has been associated with a significant decrease in mean warfarin dose requirement in at least eight studies. Several studies also suggest that possession of a variant allele is associated with an increased risk of adverse events. Other genetic factors such as polymorphisms affecting CYP3A4 or CYP1A2 may also be relevant to warfarin dose requirement. The molecular basis of warfarin resistance remains unclear but could be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to abnormal vitamin K epoxide reductase (pharmacodynamic resistance). There is less information available on genetic factors affecting other anticoagulants, but the CYP2C9 genotype is also relevant to acenocoumarol dose.

KEYWORDS

Warfarin metabolism - genetic factors - CYP2C9

REFERENCES

  • 1 Ingelman-Sundberg M, Oscarson M, McLellan R A. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment.  Trends Pharmacol Sci . 1999;  20 342-349
    CrossrefPubMedSearch in Google Scholar
  • 2 Roses A D. Pharmacogenetics and the practice of medicine.  Nature . 2000;  405 857-865
    CrossrefPubMedSearch in Google Scholar
  • 3 Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications.  Clin Pharmacokinet . 2001;  40 587-603
    CrossrefPubMedSearch in Google Scholar
  • 4 Kaminsky L S, Zhang Z Y. Human P450 metabolism of warfarin.  Pharmacol Ther . 1997;  73 67-74
    CrossrefPubMedSearch in Google Scholar
  • 5 Rettie A E, Korzekwa K R, Kunze K L. et al . Hydroxylation of warfarin by human cDNA-expressed cytochrome-P-450-a role for P-4502C9 in the etiology of (S)-warfarin drug-interactions.  Chem Res Toxicol . 1992;  5 54-59
    CrossrefPubMedSearch in Google Scholar
  • 6 Hermans J JR, Thijssen H HW. Stereoselective acetonyl side-chain reduction of warfarin and analogs-partial characterization of 2 cytosolic carbonyl reductases.  Drug Metab Dispos . 1992;  20 268-274
    PubMedSearch in Google Scholar
  • 7 Jansing R L, Chao E S, Kaminsky L S. Phase-II metabolism of warfarin in primary culture of adult rat hepatocytes.  Mol Pharmacol . 1992;  41 209-215
    PubMedSearch in Google Scholar
  • 8 He M X, Korzekwa K R, Jones J P, Rettie A E, Trager W F. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9.  Arch Biochem Biophys . 1999;  372 16-28
    CrossrefPubMedSearch in Google Scholar
  • 9 http://www.imm.ki.se/CYPalleles/ . 
  • 10 Kidd R S, Curry T B, Gallagher S, Edeki T, Blaisdell J, Goldstein J A. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin.  Pharmacogenetics . 2001;  11 803-808
    CrossrefPubMedSearch in Google Scholar
  • 11 Aithal G P, Day C P, Kesteven P JL, Daly A K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.  Lancet . 1999;  353 717-719
    CrossrefPubMedSearch in Google Scholar
  • 12 Scordo M G, Aklillu E, Yasar U, Dahl M L, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P4502C9 in a Caucasian and a black African population.  Br J Clin Pharmacol . 2001;  52 447-450
    CrossrefPubMedSearch in Google Scholar
  • 13 Rettie A E, Wienkers L C, Gonzalez F J, Trager W F, Korzekwa K R. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9.  Pharmacogenetics . 1994;  4 39-42
    CrossrefPubMedSearch in Google Scholar
  • 14 Rettie A E, Haining R L, Bajpai M, Levy R H. A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin.  Epilepsy Res . 1999;  35 253-255
    CrossrefPubMedSearch in Google Scholar
  • 15 Crespi C L, Miller V P. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase.  Pharmacogenetics . 1997;  7 203-210
    PubMedSearch in Google Scholar
  • 16 Haining R L, Hunter A P, Veronese M E, Trager W F, Rettie A E. 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 . 1996;  333 447-458
    CrossrefPubMedSearch in Google Scholar
  • 17 Shintani M, Ieiri I, Inoue K. et al . Genetic polymorphisms and functional characterization of the 5'-flanking region of the human CYP2C9 gene: in vitro and in vivo studies.  Clin Pharmacol Ther . 2001;  70 175-182
    CrossrefPubMedSearch in Google Scholar
  • 18 Leung A YH, Chow H CH, Kwong Y L. et al . Genetic polymorphism in exon 4 of cytochrome P450CYP2C9 may be associated with warfarin sensitivity in Chinese patients.  Blood . 2001;  98 2584-2587
    CrossrefPubMedSearch in Google Scholar
  • 19 Higashi M K, Veenstra D L, Kondo L ML, Wittkowsky A K, Srinouanprachanh S L, Farin F M, Rettie A E. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.  JAMA . 2002;  287 1690-1698
    CrossrefPubMedSearch in Google Scholar
  • 20 Huang J D, Guo W C, Lai M D, Guo Y L, Lambert G H. Detection of a novel cytochrome P-450 1A2 polymorphism (F21L) in Chinese.  Drug Metab Dispos . 1999;  27 98-101
    PubMedSearch in Google Scholar
  • 21 Sachse C, Brochmoller J, Bauer S, Roots I. Functional significance of a C → A polymorphism in intron I of the cytochrome P450 CYP1A2 gene tested with caffeine.  Br J Clin Pharmacol . 1999;  47 445-449
    CrossrefPubMedSearch in Google Scholar
  • 22 Nakajima M, Yokoi T, Mizutani M, Kinoshita M, Funayama M, Kamataki T. Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans.  J Biochem . 1999;  125 803-808
    PubMedSearch in Google Scholar
  • 23 Sata F, Sapone A, Elizondo G. et al . CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity.  Clin Pharmacol Ther . 2000;  67 48-56
    CrossrefPubMedSearch in Google Scholar
  • 24 Hsieh K P, Lin Y Y, Cheng C L, Lai M L, Lin M S, Siest J P, Huang J D. Novel mutations of CYP3A4 in Chinese.  Drug Metab Dispos . 2001;  29 268-273
    PubMedSearch in Google Scholar
  • 25 Dai D, Tang J, Rose R, Hodgson E, Bienstock R J, Mohrenweiser H W, Goldstein J A. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos.  J Pharmacol Exp Ther . 2001;  299 825-831
    PubMedSearch in Google Scholar
  • 26 Lamba J K, Lin Y S, Thummel K. et al . Common allelic variants of cytochrome P4503A4 and their prevalence in different populations.  Pharmacogenetics . 2002;  12 121-132
    CrossrefPubMedSearch in Google Scholar
  • 27 Rebbeck T R, Jaffe J M, Walker A H, Wein A J, Malkowicz S B. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4.  J Natl Cancer Inst . 1998;  90 1225-1229
    CrossrefPubMedSearch in Google Scholar
  • 28 Westlind A, Lofberg L, Tindberg N, Andersson T B, Ingelman-Sundberg M. Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5'-upstream regulatory region.  Biochem Biophys Res Commun . 1999;  259 201-205
    CrossrefPubMedSearch in Google Scholar
  • 29 Kuehl P, Zhang J, Lin Y. et al . Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.  Nat Genet . 2001;  27 383-391
    CrossrefPubMedSearch in Google Scholar
  • 30 Gillam E MJ, Guo Z, Ueng Y-F. et al . Expression of cytochrome P450 3A5 in Escherichia coli: effects of 5' modification, purification, reconstitution conditions, and catalytic activities.  Arch Biochem Biophys . 1995;  317 374-384
    CrossrefPubMedSearch in Google Scholar
  • 31 Margaglione M, Colaizzo D, D'Andrea G, Brancaccio V, Clampa A, Grandone E, Di Minno G. Genetic modulation of oral anticoagulation with warfarin.  Thromb Haemost . 2000;  84 775-778
    PubMedSearch in Google Scholar
  • 32 Taube J, Halsall D, Baglin T. Influence of cytochrome P-450CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment.  Blood . 2000;  96 1816-1819
    PubMedSearch in Google Scholar
  • 33 Baglin T. Avoiding overanticoagulation: pharmacogenomics or pragmatism?.  Thromb Haemost . 2001;  85 945-946
    PubMedSearch in Google Scholar
  • 34 Margaglione M, Brancaccio V, Ciampa A, Di Minno G. Reply to Rebuttal: gene variants of the cytochrome P450CYP2C9 affect oral anticoagulation with warfarin.  Thromb Haemost . 2001;  86 938
    PubMedSearch in Google Scholar
  • 35 Thijssen H HW, Verkooijen I WC, Frank H LL. The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol.  Pharmacogenetics . 2000;  10 757-760
    CrossrefPubMedSearch in Google Scholar
  • 36 Verstuyft C, Morin S, Robert A, Loriot M A, Beaune P, Jaillon P, Becquemont L. Early acenocoumarol overanticoagulation among cytochrome P4502C9 poor metabolizers.  Pharmacogenetics . 2001;  11 735-737
    CrossrefPubMedSearch in Google Scholar
  • 37 Hermida J, Zarza J, Alberca I, Montes R, Lopez M L, Molina E, Rocha E. Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450CYP2C9 on sensitivity to acenocournarol.  Blood . 2002;  99 4237-4239
    CrossrefPubMedSearch in Google Scholar
  • 38 Freeman B D, Zehnbauer B A, McGrath S, Borecki I, Buchman T G. Cytochrome P450 polymorphisms are associated with reduced warfarin dose.  Surgery . 2000;  128 281-285
    CrossrefPubMedSearch in Google Scholar
  • 39 Yasar U, Oscarson M, Eliasson E, Sjoqvist F. Mutations of the CYP2C9 gene and the response to warfarin.  Surgery . 2001;  129 384
    CrossrefPubMedSearch in Google Scholar
  • 40 Routledge P A, Shetty H GM, White J P, Collins P. Case studies in therapeutics: warfarin resistance and inefficacy in a man with recurrent thromboembolism, and anticoagulant-associated priapism.  Br J Clin Pharmacol . 1998;  46 343-346
    PubMedSearch in Google Scholar
  • 41 Hallak H O, Wedlund P J, Modi M W, Patel I H, Lewis G L, Woodruff B, Trowbridge A A. High clearance of (S)-warfarin in a warfarin-resistant subject.  Br J Clin Pharmacol . 1993;  35 327-330
    PubMedSearch in Google Scholar
  • 42 O'Reilly R A. The second reported kindred with hereditary resistance to oral anticoagulant drugs.  N Engl J Med . 1970;  282 1448-1451
    PubMedSearch in Google Scholar
  • 43 Cain D, Hutson S M, Wallin R. Warfarin resistance is associated with a protein component of the vitamin K 2,3-epoxide reductase enzyme complex in rat liver.  J Biol Chem . 1998;  80 128-133
    PubMedSearch in Google Scholar
  • 44 Wormhoudt L W, Commandeur J NM, Vermeulen N PE. Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity.  Crit Rev Toxicol . 1999;  29 59-124
    PubMedSearch in Google Scholar
  • 45 Wallin R, Hutson S M, Cain D, Sweatt A, Sane D C. A molecular mechanism for genetic warfarin resistance in the rat.  FASEB J . 2001;  15 U163-U186
    PubMedSearch in Google Scholar
  • 46 Kohn M H, Pelz H J. A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans.  Blood . 2000;  96 1996-1998
    PubMedSearch in Google Scholar
  • 47 Furuya H, Fernandez Salguero P, Gregory W, Taber H, Steward A, Gonzalez F J, Idle J R. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy.  Pharmacogenetics . 1995;  5 389-392
    CrossrefPubMedSearch in Google Scholar
  • 48 Steward D J, Haining R L, Henne K R, Davis G, Rushmore T H, Trager W F, Rettie A E. Genetic association between sensitivity to warfarin and expression of CYP2C9*3.  Pharmacogenetics . 1997;  7 361-367
    CrossrefPubMedSearch in Google Scholar
  • 49 Aithal G P, Day C P, Kesteven P JL, Daly A K. Warfarin dose requirement and CYP2C9 polymorphisms-reply.  Lancet . 1999;  353 1972-1973
    PubMedSearch in Google Scholar
  • 50 Ogg M S, Brennan P, Meade T, Humphries S E. CYP2C9*3 allelic variant and bleeding complications.  Lancet . 1999;  354 1124
    PubMedSearch in Google Scholar
  • 51 Loebstein R, Yonath H, Peleg D. et al . Interindividual variability in sensitivity to warfarin-nature or nurture?.  Clin Pharmacol Ther . 2001;  70 159-164
    CrossrefPubMedSearch in Google Scholar
  • 52 Tabrizi A R, Zehnbauer B A, Borecki I B, McGrath S D, Buchman T G, Freeman B D. The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin.  J Am Coll Surg . 2002;  194 267-273
    CrossrefPubMedSearch in Google Scholar