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.
Department of Pharmacology, Inje University College of Medicine, 633-165 Gaegum-Dong, Jin-Gu, Busan 614-735, Korea.
Chang-Woo
CW
Yeo
Su-Jun
SJ
Lee
Sang Seop
SS
Lee
Soo Kyung
SK
Bae
Eun-Young
EY
Kim
Ji-Hong
JH
Shon
Byoung Doo
BD
Rhee
Jae-Gook
JG
Shin
D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D065727:Cytochrome P-450 CYP2C8; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007723:Korea; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D055815:Young Adult
D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8