title: In vitro metabolism of phenytoin in 36 CYP2C9 variants found in the Chinese population.
abstract: Cytochrome P450 2C9 (CYP2C9) is an important member of the cytochrome P450 enzyme superfamily, with 57 CYP2C9 allelic variants being previously reported. Recently, we identified 22 novel alleles (*36 -*56 and N418T) in the Han Chinese population. This study aims to assess the catalytic activities of wild-type (CYP2C9*1) and 36 CYP2C9 allelic variants found in the Chinese population toward phenytoin (PHT) in vitro. Insect microsomes expressing CYP2C9*1 and 36 CYP2C9 variants were incubated with 1-200 μM phenytoin for 30 min at 37 °C. Then, these products were extracted and the signal detection was performed by HPLC-MS/MS. The intrinsic clearance (Vmax/Km) values of all variants, with the exception of CYP2C9*2, CYP2C9*11, CYP2C9*23, CYP2C9*29, CYP2C9*34, CYP2C9*38, CYP2C9*44, CYP2C9*46 and CYP2C9*48, were significantly different from CYP2C9*1. CYP2C9*27, *40, *41, *47, *49, *51, *53, *54, *56 and N418T variant exhibited markedly larger values than CYP2C9*1 (>152.8%), whereas 17 variants exhibited smaller values (from 48.6% to 99.9%) due to larger Km and/or smaller Vmax values than CYP2C9*1. The findings suggest that more attention should be paid on subjects carrying these infrequent CYP2C9 alleles when administering phenytoin in clinic.
authors.affiliation: Wenzhou People's Hospital, Wenzhou, Zhejiang, 325000, China.
authors.forename: Lian-Guo
authors.initials: LG
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Wenzhou People's Hospital, Wenzhou, Zhejiang, 325000, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Wenzhou People's Hospital, Wenzhou, Zhejiang, 325000, China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Xiong
authors.affiliation: Wenzhou People's Hospital, Wenzhou, Zhejiang, 325000, China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, 100730, China.
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, 100730, China. Electronic address: caijp61@vip.sina.com.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
authors.affiliation: Department of Pharmacology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: wzhhgx@aliyun.com.
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics*; D000077300:Bosentan; D002227:Carbazoles / Q000378:metabolism; D000077261:Carvedilol; D002681:China; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D010672:Phenytoin / Q000032:analysis / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014044:Tolbutamide / Q000378:metabolism
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D013449:Sulfonamides; D000077261:Carvedilol; D010672:Phenytoin; D014044:Tolbutamide; D065729:Cytochrome P-450 CYP2C9; D000077300:Bosentan
keywords: Allelic variant; CYP2C9; Catalytic activity; Chinese population; In vitro; Phenytoin