Skip to main content
SpringerLink
Log in

Interethnic and Intraethnic Variability of CYP2C8 and CYP2C9 Polymorphisms in Healthy Individuals

  • Pharmacogenomics
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Cytochrome P450 (CYP) superfamily members CYP2C8 and CYP2C9 are polymorphically expressed enzymes that are involved in the metabolic inactivation of several drugs, including, among others, antiepileptics, NSAIDs, oral hypoglycemics, and anticoagulants. Many of these drugs have a narrow therapeutic index, and growing evidence indicates a prominent role of CYP2C8 and CYP2C9 polymorphisms in the therapeutic efficacy and in the development of adverse effects among patients treated with drugs that are CYP2C8 or CYP2C9 substrates.

In this review, we summarize present knowledge on human variability in the frequency of variant CYP2C8 and CYP2C9 alleles. Besides an expected interethnic variability in allele frequencies, a large intraethnic variability exists. Among Asian subjects, for example, statistically significant differences (p < 0.0001) in CYP2C9*3 allele frequencies between Chinese and Japanese individuals have been reported. In addition, individuals from East Asia present different allele frequencies for CYP2C9*2 and CYP2C9*3 compared with South Asian subjects (p < 0.0001). Among Caucasian Europeans, statistically significant differences for the frequency of CYP2C8*3, CYP2C9*2, and CYP2C9*3 exist (p < 0.0001). This indicates that Asian individuals or Caucasian European individuals cannot be considered as homogeneous groups regarding CYP2C8 or CYP2C9 allele frequencies. Caucasian American subjects also show a large variability in allele frequencies, which is likely to be related to ethnic ancestry. A higher frequency of variant CYP2C8 and CYP2C9 alleles is expected among Caucasian Americans with South European ancestry than in individuals with North European ancestry.

The findings summarized in this review suggest that among individuals with Asian or European ancestry, intraethnic differences in the risk of developing adverse effects with drugs that are CYP2C8 or CYP2C9 substrates are to be expected. In addition, the observed intraethnic variability reinforces the need for proper selection of control subjects and points against the use of surrogate control groups for studies involving association of CYP2C8 or CYP2C9 alleles with adverse drug reactions or spontaneous diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Table II
Table III
Fig. 2
Table IV
Table V
Table VI

Similar content being viewed by others

References

  1. Meyer UA. Pharmacogenetics: five decades of therapeutic lessons from genetic diversity. Nat Rev Genet 2004; 5(9): 669–76

    Article  PubMed  CAS  Google Scholar 

  2. Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci 2004; 25(4): 193–200

    Article  PubMed  CAS  Google Scholar 

  3. Ahmadi KR, Weale ME, Xue ZY, et al. A single-nucleotide polymorphism tagging set for human drug metabolism and transport. Nat Genet 2005; 37(1): 84–9

    PubMed  CAS  Google Scholar 

  4. Walton R, Kimber M, Rockett K, et al. Haplotype block structure of the cytochrome P450 CYP2C gene cluster on chromosome 10. Nat Genet 2005; 37(9): 915–6

    Article  PubMed  CAS  Google Scholar 

  5. Altshuler D, Brooks LD, Chakravarti A, et al. A haplotype map of the human genome. Nature 2005; 437(7063): 1299–320

    Article  Google Scholar 

  6. Yasar U, Lundgren S, Eliasson E, et al. Linkage between the CYP2C8 and CYP2C9 genetic polymorphisms. Biochem Biophys Res Commun 2002; 299(1): 25–8

    Article  PubMed  CAS  Google Scholar 

  7. Martinez C, Garcia-Martin E, Blanco G, et al. The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol 2005; 59(1): 62–9

    Article  PubMed  CAS  Google Scholar 

  8. Rifkind AB, Lee C, Chang TK, et al. Arachidonic acid metabolism by human cytochrome P450s 2C8, 2C9, 2E1, and 1A2: regioselective oxygenation and evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation in human liver microsomes. Arch Biochem Biophys 1995; 320(2): 380–9

    Article  PubMed  CAS  Google Scholar 

  9. Zeldin DC, Moomaw CR, Jesse N, et al. Biochemical characterization of the human liver cytochrome P450 arachidonic acid epoxygenase pathway. Arch Biochem Biophys 1996; 330(1): 87–96

    Article  PubMed  CAS  Google Scholar 

  10. Bylund J, Kunz T, Valmsen K, et al. Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes. J Pharmacol Exp Ther 1998; 284(1): 51–60

    PubMed  CAS  Google Scholar 

  11. Nadin L, Murray M. Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes. Biochem Pharmacol 1999; 58(7): 1201–8

    Article  PubMed  CAS  Google Scholar 

  12. Marill J, Cresteil T, Lanotte M, et al. Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol Pharmacol 2000; 58(6): 1341–8

    PubMed  CAS  Google Scholar 

  13. Pfister SL, Spitzbarth N, Zeldin DC, et al. Rabbit aorta converts 15-HPETE to trihydroxyeicosatrienoic acids: potential role of cytochrome P450. Arch Biochem Biophys 2003; 420(1): 142–52

    Article  PubMed  CAS  Google Scholar 

  14. Totah RA, Rettie AE. Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharmacol Ther 2005; 77(5): 341–52

    Article  PubMed  CAS  Google Scholar 

  15. Garcia-Martin E, Martinez C, Tabares B, et al. Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther 2004; 76(2): 119–27

    Article  PubMed  CAS  Google Scholar 

  16. Blanco G, Martinez C, Garcia-Martin E, et al. Cytochrome P450 gene polymorphisms and variability in response to NSAIDs. Clin Res Regul Aff 2005; 22(2): 57–81

    Article  Google Scholar 

  17. Kirchheiner J, Tsahuridu M, Jabrane W, et al. The CYP2C9 polymorphism: from enzyme kinetics to clinical dose recommendations. Personalized Med 2004; 1(1): 63–84

    Article  CAS  Google Scholar 

  18. Kirchheiner J, Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77(1): 1–16

    Article  PubMed  CAS  Google Scholar 

  19. Cavalli-Sforza LL, Menozzi P, Piazza A. The history and geography of human genes. Princeton (NJ): Princeton University Press, 1994

    Google Scholar 

  20. Sim SC, Ingelman-Sundberg M, Daly AK, et al. Home page of the human cytochrome P450 (CYP) Allele Nomenclature Committee [online]. Available from URL: http://www.imm.ki.se/CYPalleles/default.htm [Accessed 2005 Jul 911

  21. Klose TS, Blaisdell JA, Goldstein JA. Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs. J Biochem Mol Toxicol 1999; 13(6): 289–95

    Article  PubMed  CAS  Google Scholar 

  22. Dai D, Zeldin DC, Blaisdell JA, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 2001; 11(7): 597–607

    Article  PubMed  CAS  Google Scholar 

  23. Bahadur N, Leathart JB, Mutch E, et al. CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol 2002; 64(11): 1579–89

    Article  PubMed  CAS  Google Scholar 

  24. Soyama A, Saito Y, Komamura K, et al. Five novel single nucleotide polymorphisms in the CYP2C8 gene, one of which induces a frame-shift. Drug Metab Pharmacokinet 2002; 17(4): 374–7

    Article  PubMed  CAS  Google Scholar 

  25. Hichiya H, Tanaka-Kagawa T, Soyama A, et al. Functional characterization of five novel CYP2C8 variants, G171S, R186X, R186G, K247R, and K383N, found in a Japanese population. Drug Metab Dispos 2005; 33(5): 630–6

    Article  PubMed  CAS  Google Scholar 

  26. Romkes M, Faletto MB, Blaisdell JA, et al. Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry 1991; 30(13): 3247–55

    Article  PubMed  CAS  Google Scholar 

  27. Rettie AE, Wienkers LC, Gonzalez FJ, et al. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 4(1): 39–42

    Article  PubMed  CAS  Google Scholar 

  28. Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics 1997; 7(3): 203–10

    Article  PubMed  CAS  Google Scholar 

  29. King BP, Khan TI, Aithal GP, et al. Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism. Pharmacogenetics 2004; 14(12): 813–22

    Article  PubMed  CAS  Google Scholar 

  30. Sullivan-Klose TH, Ghanayem BI, Bell DA, et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 1996; 6(4): 341–9

    Article  PubMed  CAS  Google Scholar 

  31. Imai J, Ieiri I, Mamiya K, et al. Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus. Pharmacogenetics 2000; 10(1): 85–9

    Article  PubMed  CAS  Google Scholar 

  32. Dickmann LJ, Rettie AE, Kneller MB, et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 2001; 60(2): 382–7

    PubMed  CAS  Google Scholar 

  33. Allabi AC, Gala JL, Horsmans Y, et al. Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans. Clin Pharmacol Ther 2004; 76(2): 113–8

    Article  PubMed  CAS  Google Scholar 

  34. Kidd RS, Curry TB, Gallagher S, et al. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 2001; 11(9): 803–8

    Article  PubMed  CAS  Google Scholar 

  35. Blaisdell J, Jorge-Nebert LF, Coulter S, et al. Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics 2004; 14(8): 527–37

    Article  PubMed  CAS  Google Scholar 

  36. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287(13): 1690–8

    Article  PubMed  CAS  Google Scholar 

  37. Si D, Guo Y, Zhang Y, et al. Identification of a novel variant CYP2C9 allele in Chinese. Pharmacogenetics 2004; 14(7): 465–9

    Article  PubMed  CAS  Google Scholar 

  38. Nei M, Roychoudhury AK. Evolutionary relationships of human populations on a global scale. Mol Biol Evol 1993; 10(5): 927–43

    PubMed  CAS  Google Scholar 

  39. Garte S, Gaspari L, Alexandrie AK, et al. Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev 2001; 10(12): 1239–48

    PubMed  CAS  Google Scholar 

  40. Nakajima M, Fujiki Y, Noda K, et al. Genetic polymorphisms of CYP2C8 in Japanese population. Drug Metab Dispos 2003; 31(6): 687–90

    Article  PubMed  CAS  Google Scholar 

  41. Soyama A, Saito Y, Hanioka N, et al. Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism. Biol Pharm Bull 2001; 24(12): 1427–30

    Article  PubMed  CAS  Google Scholar 

  42. Yasar U, Bennet AM, Eliasson E, et al. Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction. Pharmacogenetics 2003; 13(12): 715–20

    Article  PubMed  CAS  Google Scholar 

  43. Niemi M, Leathart JB, Neuvonen M, et al. Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide. Clin Pharmacol Ther 2003; 74(4): 380–7

    Article  PubMed  CAS  Google Scholar 

  44. Wang SL, Huang J, Lai MD, et al. Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics 1995; 5(1): 37–42

    Article  PubMed  CAS  Google Scholar 

  45. Leung AY, Liang RHS. Studies on cytochrome P450 CYP2C9 genetic polymorphism in Chinese patients receiving warfarin [abstract]. Blood 1999; 94: 108b

    Google Scholar 

  46. Gaedigk A, Casley WL, Tyndale RF, et al. Cytochrome P4502C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations. Can J Physiol Pharmacol 2001; 79(10): 841–7

    Article  PubMed  CAS  Google Scholar 

  47. Xie HG, Prasad HC, Kim RB, et al. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 2002; 54(10): 1257–70

    Article  PubMed  CAS  Google Scholar 

  48. Yu BN, Luo CH, Wang D, et al. CYP2C9 allele variants in Chinese hypertension patients and healthy controls. Clin Chim Acta 2004; 348(1-2): 57–61

    Article  PubMed  CAS  Google Scholar 

  49. Yang JQ, Morin S, Verstuyft C, et al. Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations. Fundam Clin Pharmacol 2003; 17(3): 373–6

    Article  PubMed  CAS  Google Scholar 

  50. Nasu K, Kubota T, Ishizaki T. Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics 1997; 7(5): 405–9

    Article  PubMed  CAS  Google Scholar 

  51. Inoue K, Yamazaki H, Imiya K, et al. Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4′-hydroxylation activities in livers of Japanese and Caucasian populations. Pharmacogenetics 1997; 7(2): 103–13

    Article  PubMed  CAS  Google Scholar 

  52. Goldstein JA, de Morais SM. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 1994; 4(6): 285–99

    Article  PubMed  CAS  Google Scholar 

  53. Takahashi H, Kashima T, Nomoto S, et al. Comparisons between in-vitro and in vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes. Pharmacogenetics 1998; 8(5): 365–73

    Article  PubMed  CAS  Google Scholar 

  54. Kimura M, Ieiri I, Mamiya K, et al. Genetic polymorphism of cytochrome P450s, CYP2C19, and CYP2C9 in a Japanese population. Ther Drug Monit 1998; 20(3): 243–7

    Article  PubMed  CAS  Google Scholar 

  55. Mamiya K, Ieiri I, Shimamoto J, et al. The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998; 39(12): 1317–23

    Article  PubMed  CAS  Google Scholar 

  56. Ogawa K, Suno M, Shimizu K, et al. Genotyping of cytochrome p450 isoform genes is useful for forensic identification of cadaver. Leg Med (Tokyo) 2003; 5(3): 132–8

    Article  CAS  Google Scholar 

  57. Yoon YR, Shon JH, Kim MK, et al. Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br J Clin Pharmacol 2001; 51(3): 277–80

    Article  PubMed  CAS  Google Scholar 

  58. Lee SS, Kim KM, Thi-Le H, et al. Genetic polymorphism of CYP2C9 in a Vietnamese Kinh population. Ther Drug Monit 2005; 27(2): 208–10

    Article  PubMed  CAS  Google Scholar 

  59. London SJ, Daly AK, Leathart JB, et al. Lung cancer risk in relation to the CYP2C9*1/CYP2C9*2 genetic polymorphism among African-Americans and Caucasians in Los Angeles County, California. Pharmacogenetics 1996; 6(6): 527–33

    Article  PubMed  CAS  Google Scholar 

  60. Scordo MG, Aklillu E, Yasar U, et al. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 2001; 52(4): 447–50

    Article  PubMed  CAS  Google Scholar 

  61. Allabi AC, Gala JL, Desager JP, et al. Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations. Br J Clin Pharmacol 2003; 56(6): 653–7

    Article  PubMed  CAS  Google Scholar 

  62. London SJ, Sullivan-Klose T, Daly AK, et al. Lung cancer risk in relation to the CYP2C9 genetic polymorphism among Caucasians in Los Angeles County. Pharmacogenetics 1997; 7(5): 401–4

    Article  PubMed  CAS  Google Scholar 

  63. Nafziger AN, Kim JS, Gaedigk A, et al. CYP2C9 mutant allele frequencies in a rural US Caucasian population [abstract]. Clin Pharmacol Ther 2000; 67: 120

    Google Scholar 

  64. Furuya H, Fernandez-Salguero P, Gregory W, et al. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 1995; 5(6): 389–92

    Article  PubMed  CAS  Google Scholar 

  65. Stubbins MJ, Harries LW, Smith G, et al. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996; 6(5): 429–39

    Article  PubMed  CAS  Google Scholar 

  66. Aithal GP, Day CP, Kesteven PJ, et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353(9154): 717–9

    Article  PubMed  CAS  Google Scholar 

  67. Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96(5): 1816–9

    PubMed  CAS  Google Scholar 

  68. van der Weide J, Steijns LS, van Weelden MJ, et al. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics 2001; 11(4): 287–91

    Article  PubMed  Google Scholar 

  69. Burian M, Grosch S, Tegeder I, et al. Validation of a new fluorogenic real-time PCR assay for detection of CYP2C9 allelic variants and CYP2C9 allelic distribution in a German population. Br J Clin Pharmacol 2002; 54(5): 518–21

    Article  PubMed  CAS  Google Scholar 

  70. Yasar U, Eliasson E, Dahl ML, et al. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999; 254(3): 628–31

    Article  PubMed  CAS  Google Scholar 

  71. Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, et al. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 2003; 59(4): 303–12

    Article  PubMed  CAS  Google Scholar 

  72. Scordo MG, Caputi AP, D’Arrigo C, et al. Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol Res 2004; 50(2): 195–200

    Article  PubMed  CAS  Google Scholar 

  73. Garcia-Martin E, Martinez C, Ladero JM, et al. High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur J Clin Pharmacol 2001; 57(1): 47–9

    Article  PubMed  CAS  Google Scholar 

  74. Dorado P, Berecz R, Norberte MJ, et al. CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers. Eur J Clin Pharmacol 2003; 59(3): 221–5

    Article  PubMed  CAS  Google Scholar 

  75. Topic E, Stefanovic M, Samardzija M. Association between the CYP2C9 polymorphism and the drug metabolism phenotype. Clin Chem Lab Med 2004; 42(1): 72–8

    Article  PubMed  CAS  Google Scholar 

  76. Bozina N, Granic P, Lalic Z, et al. Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat Med J 2003; 44(4): 425–8

    PubMed  Google Scholar 

  77. Hamdy SI, Hiratsuka M, Narahara K, et al. Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population. Br J Clin Pharmacol 2002; 53(6): 596–603

    Article  PubMed  CAS  Google Scholar 

  78. Aynacioglu AS, Brockmoller J, Bauer S, et al. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 1999; 48(3): 409–15

    Article  PubMed  CAS  Google Scholar 

  79. Babaoglu MO, Yasar U, Sandberg M, et al. CYP2C9 genetic variants and losartan oxidation in a Turkish population. Eur J Clin Pharmacol 2004; 60(5): 337–42

    Article  PubMed  CAS  Google Scholar 

  80. Peyvandi F, Spreafico M, Karimi M, et al. Allele frequency of CYP2C9 gene polymorphisms in Iran. Thromb Haemost 2002; 88(5): 874–5

    PubMed  CAS  Google Scholar 

  81. Bravo-Villalta HV, Yamamoto K, Nakamura K, et al. Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study. Eur J Clin Pharmacol 2005 May; 61(3): 179–84

    Article  PubMed  CAS  Google Scholar 

  82. LLerena A, Dorado P, O’Kirwan F, et al. Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards. Pharmacogenomics J 2004; 4(6): 403–6

    Article  PubMed  CAS  Google Scholar 

  83. Jose R, Chandrasekaran A, Sam SS, et al. CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population. Fundam Clin Pharmacol 2005; 19(1): 101–5

    Article  PubMed  CAS  Google Scholar 

  84. Odani A, Hashimoto Y, Otsuki Y, et al. Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther 1997; 62(3): 287–92

    Article  PubMed  CAS  Google Scholar 

  85. Ogg MS, Brennan P, Meade T, et al. CYP2C9*3 allelic variant and bleeding complications. Lancet 1999; 354(9184): 1124

    Article  PubMed  CAS  Google Scholar 

  86. Ackermann E, Cascorbi I, Sachse C, et al. Frequencies and the allelic linkage of CYP2C9 mutations in a German population, and the detection of a C/T mutation in intron 2 [abstract]. Eur J Clin Pharmacol 1997; 52: A71

    Article  Google Scholar 

  87. Yasar U, Aklillu E, Canaparo R, et al. Analysis of CYP2C9*5 in Caucasian, Oriental and black-African populations. Eur J Clin Pharmacol 2002; 58(8): 555–8

    Article  PubMed  CAS  Google Scholar 

  88. Suarez-Kurtz G, Vianna-Jorge R, Perini JA, et al. Detection of CYP2C9*5 in a white Brazilian subject. Clin Pharmacol Ther 2005; 77(6): 587–8

    Article  PubMed  CAS  Google Scholar 

  89. Soyama A, Hanioka N, Saito Y, et al. Amiodarone N-deethylation by CYP2C8 and its variants, CYP2C8*3 and CYP2C8 P404A. Pharmacol Toxicol 2002; 91(4): 174–8

    Article  PubMed  CAS  Google Scholar 

  90. Hemminki K, Forsti A. Proper controls for SNP studies? Carcinogenesis 2002; 23(8): 1405

    Article  PubMed  CAS  Google Scholar 

  91. Sanderson S, Emery J, Higginsv J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005; 7(2): 97–104

    Article  PubMed  CAS  Google Scholar 

  92. Martinez C, Blanco G, Ladero JM, et al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol 2004; 141(2): 205–8

    Article  PubMed  CAS  Google Scholar 

  93. Agundez JA. Cytochrome P450 gene polymorphism and cancer. Curr Drug Metab 2004; 5(3): 211–24

    Article  PubMed  CAS  Google Scholar 

  94. Chan AT, Tranah GJ, Giovannucci EL, et al. A prospective study of genetic polymorphisms in the cytochrome P-450 2C9 enzyme and the risk for distal colorectal adenoma. Clin Gastroenterol Hepatol 2004; 2(8): 704–12

    Article  PubMed  CAS  Google Scholar 

  95. Sachse C, Smith G, Wilkie MJ, et al. A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. Carcinogenesis 2002; 23(11): 1839–49

    Article  PubMed  CAS  Google Scholar 

  96. Tranah GJ, Chan AT, Giovannucci E, et al. Epoxide hydrolase and CYP2C9 polymorphisms, cigarette smoking, and risk of colorectal carcinoma in the Nurses’ Health Study and the Physicians’ Health Study. Mol Carcinog 2005 Sep; 44(1): 21–30

    Article  PubMed  CAS  Google Scholar 

  97. Martinez C, Garcia-Martin E, Ladero JM, et al. Association of CYP2C9 genotypes leading to high enzyme activity and colorectal cancer risk. Carcinogenesis 2001; 22 (8): 1323-6

    Google Scholar 

  98. Bigler J, Whitton J, Lampe JW, et al. CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk. Cancer Res 2001; 61(9): 3566–9

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Research at authors’ laboratories is financed by grants SAF 2003-00967 from Ministerio de Ciencia y Tecnología, FIS 02/0255 from Fondo de Investigatión Sanitaria, Instituto de Salud Carlos III, Madrid, Spain; SCSS0464 and SCSS0465 from Consejería de Sanidad y Consumo, Junta de Extremadura, Merida, Spain.

The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, School of Sciences, University of Extremadura, Badajoz, Spain

    Elena García-Martín

  2. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071, Badajoz, Spain

    Carmen Martínez &  José A. G. Agúndez

  3. Service of Gastroenterology, San Carlos University Hospital, Complutense University, Madrid, Spain

    José M. Ladero

Authors
  1. Elena García-Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carmen Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. José M. Ladero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José A. G. Agúndez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José A. G. Agúndez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

García-Martín, E., Martínez, C., Ladero, J.M. et al. Interethnic and Intraethnic Variability of CYP2C8 and CYP2C9 Polymorphisms in Healthy Individuals. Mol Diag Ther 10, 29–40 (2006). https://doi.org/10.1007/BF03256440

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256440

Keywords

Search

Navigation