Identification of new CYP2C19 variants exhibiting decreased enzyme activity in the metabolism of S-mephenytoin and omeprazole.
Although many cases of interindividual variation in the metabolism of CYP2C19 drugs are explained by the CYP2C19*2, *3, and *17, a wide range of metabolic variation still occurs in people who do not carry these genetic variants. The objectives of this study were to identify new genetic variants and to characterize functional consequences of these variants in metabolism of CYP2C19 substrates. In total, 21 single-nucleotide polymorphisms including three new coding variants, V394M, E405K, and D256N, were identified by direct DNA sequencing in 50 randomly selected subjects and in individuals who exhibited an outlier phenotype response in the omeprazole study. Recombinant proteins produced from the coding variants V394M, E405K, and D256N were prepared by using an Escherichia coli expression system and purified. Metabolism of S-mephenytoin and omeprazole by V394M was comparable with that of the wild-type protein. E405K showed a moderate decrease in metabolism of the substrates. However, D256N exhibited a significantly decreased activity in S-mephenytoin metabolism, resulting in 50 and 76% decreases in V(max) and intrinsic clearance, respectively, compared with the wild type. This variant also exhibited a significant decrease in omeprazole metabolism in vivo. CYP2C19 D256N and E405K were assigned as CYP2C19*26 and *2D, respectively, by the Cytochrome P450 Nomenclature Committee. In summary, this report characterizes the allele frequency and haplotype distribution of CYP2C19 in a Korean population and provides functional analysis of new coding variants of the CYP2C19 gene. Our findings suggest that individuals carrying CYP2C19*26 would have lower activity for metabolizing CYP2C19 substrate drugs.
Lee
Su-Jun
SJ
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University Busan Paik Hospital, Jin-gu, Busan, Korea.
Kim
Woo-Young
WY
Kim
Hyunmi
H
Shon
Ji-Hong
JH
Lee
Sang Seop
SS
Shin
Jae-Gook
JG
D000328:Adult; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D002417:Cattle; D065731:Cytochrome P-450 CYP2C19; D004789:Enzyme Activation / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D008617:Mephenytoin / Q000737:chemistry / Q000378:metabolism*; D009853:Omeprazole / Q000378:metabolism*; D011897:Random Allocation; D013379:Substrate Specificity / Q000235:genetics; D055815:Young Adult
D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin