In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population
In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population
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中国汉族人群中发现的 13 个 CYP2C9 等位基因变异体的体外和体内特征
DOI：
10.1124/dmd.114.061200
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发表时间：
2015-04-01
影响因子：
3.9
通讯作者：
Cai, Jian-Ping
中科院分区：
文献类型：
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作者：
Hu, Guo-Xin;Pan, Pei-Pei;Cai, Jian-Ping
本研究在2127名中国人中共检测到35种CYP 2C 9等位基因变异，其中21种为中国人群首次报道。本研究的目的是在体外和体内表征13种CYP 2C 9等位基因变体。不同类型的CYP 2C 9变异体在COS-7细胞中高表达，并加入50 μM甲苯磺丁脲作为探针底物，以评估其体外代谢能力。随后，甲苯磺丁脲及其代谢产物的浓度在血浆和尿液中的不同类型的基因型的个体内通过HPLC测定，以评估在体内的催化活性的13个突变体CYP 2C 9蛋白。我们的结果显示，与 *1/*1野生型受试者相比，*1/*40基因型受试者的口服清除率（CL/F）增加，而 *1/*3，*1/*13，* 3/*3，*3/*13，*1/*16，*1/*19，*1/*34，*1/*42，*1/*45，*1/*46，*1/*27、*1/*29、*1/*40和 * 1/* 41基因型的CL/F值与 *1/*27、*1/*29、*1/*40和 *1/*41基因型的CL/F值相似。当在COS-7细胞中表达时，CYP 2C 9变体显示与临床研究结果相似的模式。研究表明，除了两个典型的缺陷等位基因 *3和 *13外，7个CYP 2C 9等位基因变体（*16、*19、*34、*42、*45、*46和 *48）在体外和体内均对酶活性产生缺陷效应。在临床上，应密切关注这些缺陷等位基因的患者。
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.