Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data

Abstract

The discovery of six distinct polymorphisms in the genetic sequence encoding for the cytochrome P450 2C9 (CYP2C9) protein has stimulated numerous investigations in an attempt to characterize their population distribution and metabolic activity. Since the CYP2C9*1, *2 and *3 alleles were discovered first, they have undergone more thorough investigation than the recently identified *4, *5 and *6 alleles. Population distribution data suggest that the variant *2 and *3 alleles are present in approximately 35% of Caucasian individuals; however, these alleles are significantly less prevalent in African-American and Asian populations. In-vitro data have consistently demonstrated that the CYP2C9*2 and *3 alleles are associated with significant reductions in intrinsic clearance of a variety of 2C9 substrates compared with CYP2C9*1; however, the degree of these reductions appear to be highly substrate-dependent. In addition, multiple in-vivo investigations and clinical case reports have associated genotypes expressing the CYP2C9*2 and *3 alleles with significant reductions in both the metabolism and daily dose requirements of selected CYP2C9 substrates. Individuals expressing these variant genotypes also appear to be significantly more susceptible to adverse events with the narrow therapeutic index agents warfarin and phenytoin, particularly during the initiation of therapy. These findings have subsequently raised numerous questions regarding the potential clinical utility of genotyping for CYP2C9 prior to initiation of therapy with these agents. However, further clinical investigations evaluating the metabolic consequences in individuals expressing the CYP2C9*2, *3, *4, *5, or *6 alleles are required before large-scale clinical genotyping can be recommended.

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

“…Finally, CYP2C9*6 variant allele has been identified; this is a new null polymorphism containing an adenine base pair deletion at nucleotide 818, which results in a premature stop codon and a truncated inactive protein. 8,9 The genotypic features of the CYP2C9 gene have been studied in several ethnic groups (Table 1); very low frequency of alleles CYP2C9*2 and *3 has been found among Oriental populations. We have previously shown the genetic polymorphism of CYP2C9 among Spaniards.…”

Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin

“…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 ).…”

“…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 ). We have recently studied the population differences of hepatic CYP2C9 activity using CL po,u for (S)-warfarin as a specific in vivo probe for the CYP isoform between Caucasians and Japanese patients and found that the population mean for body weightnormalized CL po,u for (S)-warfarin obtained from Japanese patients was significantly greater than that for Caucasian patients.…”

“…We have recently studied the population differences of hepatic CYP2C9 activity using CL po,u for (S)-warfarin as a specific in vivo probe for the CYP isoform between Caucasians and Japanese patients and found that the population mean for body weightnormalized CL po,u for (S)-warfarin obtained from Japanese patients was significantly greater than that for Caucasian patients. 14 Considering greater allelic frequencies of CYP2C9*2 and CYP2C9*3 in Caucasians than in Japanese patients, 8,9 one may assume that population differences in the allelic frequencies of CYP2C9*2 and CYP2C9*3 between Caucasians and Japanese patients may account at least partly for the above-described population difference in the metabolic activity for (S)-warfarin. However, comparisons of CL po,u for (S)-warfarin between the genotype-matched Japanese patients and Caucasians with the homozygous wild-type CYP2C9 genotype revealed that Japanese patients still had a significantly greater body weight-normalized CL po,u than the Caucasians.…”

“…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.…”