RT Journal Article
SR Electronic
T1 In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 561
OP 569
DO 10.1124/dmd.114.061200
VO 43
IS 4
A1 Hu, Guo-Xin
A1 Pan, Pei-Pei
A1 Wang, Zeng-Shou
A1 Yang, Li-Ping
A1 Dai, Da-Peng
A1 Wang, Shuang-Hu
A1 Zhu, Guang-Hui
A1 Qiu, Xiang-Jun
A1 Xu, Tao
A1 Luo, Jun
A1 Lian, Qing-Quan
A1 Ge, Ren-Shan
A1 Cai, Jian-Ping
YR 2015
UL http://dmd.aspetjournals.org/content/43/4/561.abstract
AB 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.