Discovery of a novel allelic variant of CYP2C8, CYP2C8*11, in Asian populations and its clinical effect on the rosiglitazone disposition in vivo

The objectives of this study were to identify the genetic variants of CYP2C8 , analyze CYP2C8 single nucleotide polymorphisms (SNPs), and characterize their functional consequences in the CYP2C8 substrate drug rosiglitazone in humans. The direct full sequencing of CYP2C8 genomic DNA was performed in a Korean population ( n = 50). A total of 17 CYP2C8 variants including a novel coding variant (E274Stop) were identified. The novel CYP2C8 E274Stop variant was assigned as CYP2C8 * 11 by the Human Cytochrome P450 ( CYP ) Allele Nomenclature Committee. Seventeen SNPs were used to characterize linkage disequilibrium, haplotype structures, and haplotype tagging SNPs. Genotyping for CYP2C8 * 11 in an extended set of Koreans ( n = 400), whites ( n = 100), Han Chinese ( n = 348), Vietnamese ( n = 100), and African Americans ( n = 93) was performed by a newly developed pyrosequencing method. The frequency of CYP2C8 * 11 was 0.3% in Koreans, 1% in Vietnamese, and 0.14% in Chinese. However, none of the whites or African Americans contained the CYP2C8 * 11 allele. Subjects with CYP2C8 * 1 /* 11 exhibited higher plasma concentration-time profiles of rosiglitazone than those of nine control subjects carrying CYP2C8 * 1 /* 1 . The area under the concentration-time curve and peak plasma concentration of rosiglitazone in individuals carrying CYP2C8 * 1 /* 11 ( n = 5) were 54 and 34% higher than the mean values observed in the control subjects carrying CYP2C8 * 1 /* 1 ( P = 0.015 and P = 0.025, respectively). In summary, this is the first report to characterize the allele frequency and haplotype distribution of CYP2C8 in a Korean population, and it provides functional analysis of a new variant CYP2C8 * 11 . Our findings suggest that individuals carrying CYP2C8 * 11 , a null allele found in Asians only, may have lower activity for metabolizing CYP2C8 substrate drugs.