title: In vitro and in vivo characterization of 13 CYP2C9 allelic variants found in Chinese Han population.
abstract: Our previous study detected totally 35 CYP2C9 allelic variants in 2127 Chinese subjects, of whom 21 novel alleles were reported for the first time in Chinese populations. The aim of the present study was to characterize the 13 CYP2C9 allelic variants both in vitro and in vivo. Different types of CYP2C9 variants were highly expressed in COS-7 cells, and 50 μM tolbutamide was added as the probing substrate to evaluate their metabolic abilities in vitro. Subsequently, the concentrations of tolbutamide and its metabolite in the plasma and urine within individuals with different types of genotypes were determined by HPLC to evaluate the catalytic activity of the 13 mutant CYP2C9 proteins in vivo. Our results showed that compared with *1/*1 wild-type subjects, subjects with *1/*40 genotype showed increased oral clearance (CL/F), whereas individuals with *1/*3, *1/*13, *3/*3, *3/*13, *1/*16, *1/*19, *1/*34, *1/*42, *1/*45, *1/*46, and *1/*48 genotype exhibited significantly decreased CL/F, and those with *1/*27, *1/*29, *1/*40, and *1/*41 genotype presented similar CL/F value. When expressed in COS-7 cells, the CYP2C9 variants showed similar pattern to the results in clinical study. The study suggests that, besides two typical defective alleles, *3 and *13, seven CYP2C9 allelic variants (*16, *19, *34, *42, *45, *46, and *48) cause defective effects on the enzymatic activities both in vitro and in vivo. In clinic, patients with these defective alleles should be paid close attention to.
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Pan
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Zeng-Shou
authors.initials: ZS
authors.lastname: Wang
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Yang
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Shuang-Hu
authors.initials: SH
authors.lastname: Wang
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Zhu
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Qiu
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.).
authors.forename: Qing-Quan
authors.initials: QQ
authors.lastname: Lian
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.) caijp61@vip.sina.com r_ge@yahoo.com.
authors.forename: Ren-Shan
authors.initials: RS
authors.lastname: Ge
authors.affiliation: Testing and Analysis Laboratory for Phase I Clinical Trials (G.-X.H., P.-P.P., S.-H.W., T.X., J.L.) and Second Affiliated Hospital and Yuying Children's Hospital (Z.-S.W., G.-H.Z., Q.-Q.L., R.-S.G.), Wenzhou Medical University, Wenzhou, P.R. China; Department of Pharmacy, Beijing Hospital, Ministry of Health, Beijing, P.R. China (L.-P.Y.); Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, P.R. China (D.-P.D., J.-P.C.); and Medical College of Henan University of Science and Technology, Luoyang, P.R. China (X.-J.Q.) caijp61@vip.sina.com r_ge@yahoo.com.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
mesh_terms: D000483:Alleles; D000818:Animals; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D019556:COS Cells; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D010957:Plasmids; D014044:Tolbutamide / Q000097:blood / Q000652:urine; D014162:Transfection
chemical_list: D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9