Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus

Imai, Jun; Ieiri, Ichiro; Mamiya, Kohsuke; Miyahara, Sayaka; Furuumi, Hiroyasu; Nanba, Eiji; Yamane, Masayuki; Fukumaki, Yasuyuki; Ninomiya, Hideaki; Tashiro, Nobutada; Otsubo, Kenji; Higuchi, Shun

doi:10.1097/00008571-200002000-00011

Cited by 130 publications

(83 citation statements)

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“…10 CYP2C9*4, *5 and *6 alleles were studied using primers and restriction enzymes described elsewhere. [15][16][17] Statistics The CYP2C9 allele frequencies were compared by using the Fisher's exact test. Hardy-Weinberg equilibrium was determined by comparing the genotype frequencies with the expected values using a contingency table w 2 statistic with Yates's correction.…”

Section: Cyp2c9 Genotypingmentioning

confidence: 99%

Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards

et al. 2004

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Interethnic differences in cytochrome P450 polymorphism might be responsible, at least in part, for the variations in drug disposition between ethnic groups. Of the various CYP2C9 alleles, CYP2C9*2 and CYP2C9*3 have been reported to have altered catalytic activities compared to the wild-type CYP2C9*1. The present study is aimed at analysing the CYP2C9 polymorphism in a Mexican-American compared with a Spanish population. Differences between the two populations of healthy volunteers, Mexican-Americans (n ¼ 98 subjects) and Spaniards (n ¼ 102 subjects), regarding the CYP2C9 allele frequencies have been found. CYP2C9 genotypes among the studied Mexican-American population are in equilibrium. The 95% CI were, respectively, 0.81-0.90 for CYP2C9*1 (n ¼ 169), 0.05-0.13 for CYP2C9*2 (n ¼ 16) and 0.031-0.10 for CYP2C9*3 (n ¼ 11). CYP2C9*4, *5 and *6 were found in none of the studied subjects. The frequency of CYP2C9*2 was lower among Mexican-Americans compared to Spaniards (Po0.05). The obtained frequency of CYP2C9 alleles is compatible with the genomic assembly of the constitutive potential ethnic origin of this population, and supports the need of pharmacogenetic studies for optimizing the recommended drug dosages to Mexican-Americans. INTRODUCTIONThe genetic polymorphism of the cytochrome P450 enzymes is one of the major determinants of the interindividual variability of pharmacokinetics and drug response. Human cytochrome P450 (CYP) is a group of haemoproteins catalysing the oxidative phase I metabolism of many exogenous and endogenous substrates. 1 Among them, the CYP2 family, especially the CYP2C subfamily, is large and complex. 2 CYP2C9 constitutes approximately 20% of the total human liver microsome CYP protein content, and metabolizes approximately 10% of therapeutically important drugs. [3][4][5] The CYP2C9 isoenzyme is primarily responsible for the oxidative metabolism of several clinically important compounds, including the narrow therapeutic index drugs warfarin and phenytoin, and other routinely prescribed compounds such as losartan, tolbutamide and numerous nonsteroidal anti-inflammatory drugs such as ibuprofen, piroxicam, tenoxicam and diclofenac. 5 CYP2C9 exhibits marked interindividual variability in its expression and catalytic activity due to functionally significant genetic variations. This can result in either drug toxicity (eg, warfarin-induced bleeding complications) or

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Section: Cyp2c9 Genotypingmentioning

confidence: 99%

Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards

et al. 2004

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“…We critically reappraised their findings using their primers originally reported by Stubbins et al 43 and the other primers by Sullivan-Klose et al 44 that were validated by us and others. [12][13][14]16 We found that the nucleotide sequences of the PCR products amplified by the primers of Leung et al 32 and Stubbins et al 43 differed from those amplified by the latter primers 44 and the authentic DNA sequence of CYP2C9 exon 4. Using the latter PCR primers we found no SNPs in exon 4 of CYP2C9 in Japanese patients (unpublished data).…”

Section: Effects Of Cyp2c9 Genotypes On (S)-warfarin Metabolismmentioning

confidence: 76%

“…Population differences in CYP2C9 activity and allelic frequencies of CYP2C9 variants There are substantial differences in the allelic frequencies of CYP2C9 variants, at least for CYP2C9*2 and CYP2C9*3 alleles, across different ethnic populations: the respective allelic frequencies of CYP2C9*2 and CYP2C9*3 in African-Americans (1-3.6% and 0.5-1.5%, respectively) and Asians (0% and 1.7-5%, respectively) tended to be lower than the corresponding values of Caucasians (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).1% and 5.3-10%, respectively). 8,9 As the enzyme activities of CYP2C9 variant proteins are reduced as compared with the wild-type protein 42 at least in in vitro experiments, there is a possibility that the population differences in the allelic frequencies of distinct CYP2C9 variants may emerge as those in certain phenotypic traits of CYP2C9 (eg, CL po,u ).…”

Section: Effects Of Cyp2c9 Genotypes On (S)-warfarin Metabolismmentioning

confidence: 99%

“…Among the 11 variant alleles of CYP2C9 so far reported, 7 CYP2C9*2 and CYP2C9*3 would be most important in the light of their influence on in vitro and in vivo metabolic activities and allelic frequencies in different ethnic populations. [8][9][10][11][12][13][14][15] CYP2C9*4 16 has been detected so far in only one Japanese patient whose phenytoin clearance was shown to be substantially reduced as compared with those possessing CYP2C9*1/*1. The allelic frequency of this variant should be very low in Japanese and no information is available in Caucasian and African-American populations.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin

Takahashi

Echizen

2003

Pharmacogenomics J

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“…As indicated below, the population distributions of CYP2C9 and VKORC1 genotype vary by ethnicity. 17,26,27 The degree to which differences in prevalence in different populations will influence the clinical utility of testing within those populations remains unclear.…”

Section: Pharmacogenetic Testing For Warfarin Usementioning

confidence: 99%

Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin

Flockhart

Gage

Gandolfi

et al. 2008

Genetics in Medicine

205

138

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Warfarin (Coumadin) is a potent drug that when used judiciously and monitored closely, leads to substantial reductions in morbidity and mortality from thromboembolic events. However, even with careful monitoring, initiation of warfarin dosing is associated with highly variable responses between individuals and challenges achieving and maintaining levels within the narrow therapeutic range that can lead to adverse drug events. Variants of two genes, CYP2C9 and VKORC1, account for 30 -50% of the variability in dosing of warfarin; thus, many believe that testing of these genes will aid in warfarin dosing recommendations. Evidence about this test is evolving rapidly, as is its translation into clinical practice. In an effort to address this situation, a multidisciplinary expert group was organized in November 2006 to evaluate the role of CYP2C9 and VKORC1 testing in altering warfarin-related therapeutic goals and reduction of adverse drug events. A recently completed Rapid-ACCE (Analytical, Clinical Validity, Clinical Utility, and Ethical, Legal, and Social Implications) Review, commissioned to inform this work group, was the foundation for this analysis. From this effort, specific recommendations for the appropriate use of CYP2C9 and VKORC1 testing were developed and are presented here. The group determined that the analytical validity of these tests has been met, and there is strong evidence to support association between these genetic variants and therapeutic dose of warfarin. However, there is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients.Prospective clinical trials are needed that provide direct evidence of the benefits, disadvantages, and costs associated with this testing in the setting of initial warfarin dosing. Although the routine use of warfarin genotyping is not endorsed by this work group at this time, in certain situations, CYP2C9 and VKORC1 testing may be useful, and warranted, in There is perhaps no drug whose therapeutic range is functionally as narrow as that of warfarin. Warfarin has a very large marketplace with over 30 million prescriptions in the United States in 2004, including up to a million new patients initiated on therapy each year. Although effective in reducing thrombotic events, warfarin's use is associated with 800 reports to the From the

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Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus

Cited by 130 publications

References 10 publications

Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards

Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards

Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin

Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin

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