title: Functional Characterization of Human CYP2C9 Allelic Variants in COS-7 Cells.
abstract: Variability in activity of CYP2C9, which is involved in the metabolism of approximately 15% of current therapeutic drugs, is an important contributor to interindividual differences in drug response. To evaluate the functional alternations of CYP2C9(*)2, CYP2C9(*)3, CYP2C9(*)8, CYP2C9(*)11 and CYP2C9(*)31, identified in our previous study in Chinese Han population, allelic variants as well as the wild-type CYP2C9 were transiently expressed in COS-7 cells. Kinetic parameters (Km, Vmax, and Clint) for S-warfarin 7-hydroxylation by these recombinant CYP2C9s were determined. Relative to CYP2C9.1, recombinant CYP2C9.3 and CYP2C9.11 exhibited significantly higher Km values, and all allelic variants showed significantly decreased Vmax and Clint values. Among all allelic variants, catalytic activity of CYP2C9.3 and CYP2C9.11 reduced the most (8.2% and 9.8% of Clint ratio, respectively; P < 0.001). These findings should be useful for predicting the phenotype profiles of CYP2C9 in Chinese Han population, comparing the functional results of these alleles accurately, and finally optimizing pharmacotherapy of drug treatment.
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Du
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Yucai
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Pharmacy, Shanghai Pulmonary Hospital Shanghai, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Shen
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China; Institutes of Biomedical Sciences, Fudan UniversityShanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: Bio-X Institutes, Shanghai Jiao Tong UniversityShanghai, China; Shanghai Genome Pilot Institutes for Genomics and Human HealthShanghai, China.
authors.forename: Shengying
authors.initials: S
authors.lastname: Qin
keywords: Chinese Han; HPLC (high-performance/pressure liquid chromatography); S-warfarin; cytochrome P450; genetic polymorphisms; in vitro models; pharmacokinetics