Analysis of CYP2C9*5 in Caucasian, Oriental and Black-African populations

Yaşar, Ümit; Aklillu, Eleni; Canaparo, Roberto; Sandberg, Mia; Sayi, Jane; Roh, Hyung‐Keun; Wennerholm, Agneta

doi:10.1007/s00228-002-0518-6

Cited by 49 publications

(38 citation statements)

References 30 publications

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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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“…CYP2C9 is subject to genetic polymorphism, and compared with the "wild-type" allele CYP2C9*1, the allelic variants characterized to date (www.imm.ki.se/cypalleles) have all been associated with impaired CYP2C9-dependent drug metabolism. There are considerable ethnic differences in the distribution of allelic variants (Kimura et al, 1998;Scordo et al, 2001;Yasar et al, 2002a). In whites, the predominant and best-studied variants, CYP2C9*2 and CYP2C9*3, occur at a frequency of 8 to 12.5% and 3 to 8.5%, respectively (Yasar et al, 1999).…”

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confidence: 99%

The Impact of Cyp2c9 Genetics and Oral Contraceptives on Cytochrome P450 2c9 Phenotype

Sandberg¹,

Johansson²,

Christensen³

et al. 2004

Drug Metab Dispos

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ABSTRACT:CYP2C9-dependent drug metabolism is subject to large interindividual variation. To some extent, this is explained by genetic polymorphism with expression of enzyme variants that differ in catalytic activity. The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP2C9 gene in metabolic outliers. A study population of 126 healthy white subjects were recruited and genotyped for the variant alleles, CYP2C9*1-3. In CYP2C9 phenotyping with losartan, three subpopulations were distinguished that differed in the number of CYP2C9*3 alleles (0, 1, or 2). A three-fold higher metabolic ratio (MR; urinary losartan/carboxymetabolite) was found comparing CYP2C9*1/*3 (n ‫؍‬ 20) to CYP2C9*1/*1 (n ‫؍‬ 81), but there was considerable variation within each genotype. Subjects genotyped as CYP2C9*1/*1, but with an unexpectedly slow oxidation of losartan, were selected for DNA-sequencing analysis of the CYP2C9 gene. Interestingly, single nucleotide polymorphisms (SNPs) could not be identified either in the 5-flanking region, the nine exons, or exon-intron boundaries. However, sequencing of the CYP2C9 gene was also carried out in patients genotyped as CYP2C9*1/*1 but with an exceptionally low steady-state clearance of S-warfarin. Here, five different SNPs were identified. In further analysis of the healthy volunteers, it became evident that women on oral contraceptives (OCs) had slower oxidation of losartan (MR of losartan: 1.7) than women without OCs (MR of losartan: 0.86). This novel finding was not explained by a different frequency of variant alleles. In summary, CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP2C9 activity.

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“…The allelic frequency of this variant should be very low in Japanese and no information is available in Caucasian and African-American populations. CYP2C9*5 was detected in five of 110 African-American 17 and three of 183 Tanzanians, 18 but none in Caucasian or Asians. Although no information is available for the in vivo enzyme activity of CYP2C9*5 at present, recombinant proteins of CYP2C9*5 and CYP2C9*4 exhibited markedly reduced enzyme activities as compared with that of the wild-type CYP2C9 in vitro.…”

Section: Introductionmentioning

confidence: 91%

“…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%