Advances in study of CYP2C9 gene polymorphisms and its functional significances

Abstract

Abstract: Cytochrome P-450 2C9(CYP2C9) is a major drug-metabolizing enzyme in human liver and contributes to metabolism of about 10% of therapeutically usual drugs, including one with narrow therapeutic index.The human CYP2C9 gene is highly polymorphic, having many single nucleotide polymorphisms in promoters and coding regions.To date, at least 30 non-synonymous CYP2C9 alleles have been identified. This review summarizes recent advances in the study of CYP2C9 about the structure-function relationship, the functional significance of various CYP2C9 alleles in vitro and in vivo, and the frequency of CYP2C9 alleles among different populations.

Key words: CYP2C9, gene polymorphism, mutant allele, function

CLC Number:

R969

LI Zhi, WANG Guo, ZHOU Hong-hao. Advances in study of CYP2C9 gene polymorphisms and its functional significances[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(6): 601-609.

References

[1] Kirchheiner J, Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms[J]. Clin Pharmacol Ther, 2005, 77(1): 1-16.
[2] Human Cytochrome P450 (CYP) Allele Nomenclature Committee home page[EB OL]. (2004) [2007-06-30]. http://www.imm.ki.se/CYPalleles.
[3] Al-Dosari MS, Knapp JE, Liu D. Activation of human CYP2C9 promoter and regulation by CAR and PXR in mouse liver[J]. Mol Pharm, 2006, 3(3): 322-328.
[4] 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[J]. Clin Pharmacol Ther, 2001, 70(2): 175-182.
[5] Takahashi H, Ieiri I, Wilkinson GR, et al. 5'-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients[J]. Blood, 2004, 103(8): 3055-3057.
[6] Xiang SH, Parsons HK, Murray M. Identification of a novel transcriptional silencer in the protein-coding region of the human CYP2C9 gene[J]. Gene, 1998, 209(12): 123-129.
[7] Ged C, Umbenhauer DR, Bellew TM, et al. Characterization of cDNAs, mRNAs, and proteins related to human liver microsomal cytochrome P450 (s)-mephenytoin 4′-hydroxylase[J]. Biochemistry, 1988, 27 (18): 6929-6940.
[8] Wang SL, Huang JD, Lai MD, et al. Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese[J]. Pharmacogenetics, 1995, 5(1): 37-42.
[9] 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[J]. Pharmacogenetics, 2000, 10(1): 85-89.
[10] Xie HG, Prasad H, Landau R, et al. Frequency of the defective CYP2C9 variant alleles in different ethnic groups [J]. Clin Pharmacol Ther, 2002, 71(2): 102.
[11] Kidd RS, Curry TB, Gallagher S, et al. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin[J]. Pharmacogenetics, 2001, 11(9): 803-808.
[12] Blaisdell J, Jorge-Nebert LF, Coulter S, et al. Discovery of new potentially defective alleles of human CYP2C9[J]. Pharmacogenetics, 2004, 14(8): 527-537.
[13] Si D, Guo Y, Zhang Y, et al. Identification of a novel variant CYP2C9 allele in Chinese[J]. Pharmacogenetics, 2004, 14(7): 465-469.
[14] Zhao F, Loke C, Rankin SC, et al. Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose[J]. Clin Pharmacol Ther, 2004, 76(3): 210-219.
[15] Veenstra DL, Blough DK, Higashi MK, et al. CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes[J]. Clin Pharmacol Ther, 2005, 77(5): 353-364.
[16] Herman D, Peternel P, Stegnar M, et al. A novel sequence variant in exon 7 of CYP2C9 gene (CYP2C9 * 24) in a patient on warfarin therapy [J]. Thromb Haemost, 2006, 95(1): 192-194.
[17] Maekawa K, Fukushima-Uesaka H, Tohkin M, et al. Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese [J]. Pharmacogene Genomics, 2006, 16(7): 497-514.
[18] Leung AYH, Chow HCH, Wong YLK, et al. Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients [J]. Blood, 2001, 98(8): 2584-2587.
[19] Ieiri I, Tainaka H, Morita T, et al. Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis [J]. Ther Drug Monit, 2000, 22(3): 237-244.
[20] Crespi CL, Miller VP. The R144C change in the CYP2C9 *2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase[J]. Pharmacogenetics, 1997, 7(3): 203-210.
[21] Iida I, Miyata A, Arai M, et al. Catalytic roles of CYP2C9 and its variants (CYP2C9 * 2 and CYP2C9 * 3) in lornoxicam 5'-hydroxy lation[J]. Drug Metab Dispos, 2004, 32(1): 7-9.
[22] Yamazaki H, Inoue K, Chiba K, et al. Comparative studies on the catalytic roles of cytochrome P4502C9 and its Cys-and Leu-variants in the oxidation of warfarin, flurbiprofen, and diclofenac by human liver microsomes[J]. Biochem Pharmacol, 1998, 56(2): 243-251.
[23] Rettie AE, Haining RL, Bajpa M, et al. A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin[J]. Epilepsy Res, 1999, 35(3): 253-255.
[24] Dickmann LJ, Rettie AE, Kneller MB, et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C9 * 5) expressed among African Americans [J]. Mol Pharmacol, 2001, 60(2): 382-387.
[25] Guo Y, Wang Y, Si D, et al. Catalytic activities of human cytochrome P450 2C9 * 1, 2C9 * 3 and 2C9 * 13 [J]. Xenobiotica, 2005, 35(9): 853-861.
[26] DeLozier TC, Lee SC, Coulter SJ, et al. Functional characterization of novel allelic variants of CYP2C9 recently discovered in southeast Asians[J]. J Pharmacol Exp Ther, 2005, 315(3): 1085-1090.
[27] Wiwanitkit V. Pharmacogenomic effect of cytochrome P450 2C9 polymorphisms in different populations[J]. Clin Appl Thromb Hemost, 2006, 12(2): 219-222.
[28] Takahashi H, Kashima T, Nomoto S. 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[J]. Pharmacogenetics, 1998, 8(5): 365-373.
[29] Kidd RS, Straughn AB, Meyer MC, et al. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9 * 3 allele[J]. Pharmacogenetics, 1999, 9(1): 71-80.
[30] Tabrizi AR, McGrath SD, Blinder MA, et al. Extreme warfarin sensitivity in siblings associated with multiple cytochrome P450 polymorphisms[J]. Am J Hematol, 2001, 67(2): 144-146.
[31] Yasar U, Forslund-Bergengren C, Tybring G, et al. Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype[J]. Clin Pharmacol Ther, 2002, 71(1): 89-98.
[32] Allabi AC, Gala JL, Horsmans Y, et al. Functional impact of CYP2C9 * 5, CYP2C9 * 6, CYP2C9 * 8, and CYP2C9 * 11 in vivo among black Africans[J]. Clin Pharmacol Ther, 2004, 76(2): 113-118.
[33] Kidd RS, Curry TB, Gallagher S, et al. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin[J]. Pharmacogenetics, 2001, 11(9): 803-808.
[34] Guo Y, Zhang Y, Wang Y, et al. Role of CYP2C9 and its variants (CYP2C9 * 3 and CYP2C9 * 13) in the metabolism of lornoxicam in humans[J]. Drug Metab Dispos, 2005, 33(6): 749-753.
[35] Mizutani T. PM frequencies of major CYPs in Asians and Caucasians[J]. Drug Metab, 2003, 35(2/3): 99-106.
[36] Hong X, Zhang S, Mao G, et al. CYP2C9 * 3 allelic variant is associated with metabolism of irbesartan in Chinese population[J]. Eur J Clin Pharmacol, 2005, 61(9): 627-634.
[37] Bae JW, Kim HK, Kim JH, et al. Allele and genotype frequencies of CYP2C9 in a Korean population[J]. Br J Clin Pharmacol, 2005, 60(4): 418-422.
[38] Nakai K, Habano W, Nakai K, et al. Ethnic differences in CYP2C9 * 2 (Arg144Cys) and CYP2C9 * 3 (Ile359Leu) genotypes in Japanese and Israeli populations [J]. Life Sci, 2005, 78(1): 107-111.
[39] Scordo MG, Aklillu E, Yasar U, et al. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population[J]. Br J Clin Pharmacol, 2001, 52 (4): 447-450.
[40] Garcia-Martin E, Martinez C, Ladero JM, et al. High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population[J]. Eur J Clin Pharmacol, 2001, 57(1): 47-49.
[41] Yang JQ, Morin S, Verstuyft C, et al. Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations[J]. Fundam Clin Pharmacol, 2003, 17 (3): 373-376.
[42] Hong X, Zhang S, Mao G, et al. CYP2C9 * 3 allelic variant is associated with metabolism of irbesartan in Chinese population[J]. Eur J Clin Pharmacol, 2005, 61(9): 627-634.
[43] Nafziger AN, Kim JS, Gaedigk A, et al. CYP2C9 mutant allele frequencies in a rural US Caucasian population[J]. Clin Pharmacol Ther, 2000, 67(2): 120-124.
[44] Gaedigk A, Casley WL, Tyndale RF, et al. Cytochrome P4502C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations[J]. Can J Physiol Pharmacol, 2001, 79(10): 841-847.
[45] Dickmann LJ, Rettie AE, Kneller MB, et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C9 * 5) expressed among African Americans [J]. Mol Pharmacol, 2001, 60(2): 382-387.
[46] Weibert RT, Palinkas LA. Differences in warfarin dose requirements between Asian and Caucasian patients[J]. Clin Pharmacol Ther, 1991, 49(3): 151.
[47] Yu HCM, Chan TYK, Critchley JAJH, et al. Factors determining the maintenance dose of warfarin in Chinese patients[J]. Q J Med, 1996, 89(2): 127-135.
[48] Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin[J]. Pharmacol Ther, 1997, 73(1): 67-74.
[49] Takahashi H, Kashima T, Nomizo Y, et al. Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes [J]. Clin Pharmacol Ther, 1998, 63(5): 519-528.
[50] Takahashi H, Wilkinson GR, Caraco Y, et al. Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients[J]. Clin Pharmacol Ther, 2003, 73(3): 253-263.
[51] White RH, Beyth RJ, Zhou H, et al. Major bleeding after hospitalization for deep-venous thrombosis[J]. Am JMed, 1999, 107(5): 414-424.