In vitro metabolism of phenytoin in 36 CYP2C9 variants found in the Chinese population

• Published in: Chemico-biological interactions Vol. 253; pp. 93 - 99
• Main Authors: Chen, Lian-Guo, Wang, Zhe, Zhu, Yuan, Xiong, Jian-Hua, Sun, Li-Rong, Dai, Da-Peng, Cai, Jian-Ping, Hu, Guo-Xin
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 25.06.2016
• Subjects: Alleles; Allelic variant; Asian Continental Ancestry Group - genetics; Carbazoles - metabolism; Catalytic activity; China; Chinese population; Chromatography, High Pressure Liquid; CYP2C9; Cytochrome P-450 CYP2C9 - genetics; Cytochrome P-450 CYP2C9 - metabolism; Humans; In vitro; Kinetics; Phenytoin; Phenytoin - analysis; Phenytoin - metabolism; Polymorphism, Genetic; Propanolamines - metabolism; Sulfonamides - metabolism; Tandem Mass Spectrometry; Tolbutamide - metabolism; Chinese population; CYP2C9; Catalytic activity; In vitro; Phenytoin; Allelic variant
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2016.04.040

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. •We recently identified 22 novel CYP2C9 alleles in the Han Chinese population.•We assess the catalytic activities of 36 CYP2C9 alleles variants toward phenytoin in vitro.•There are 17 variants showed decreased catalytic activity toward phenytoin.