Gene polymorphisms and contents of cytochrome P450s have only limited effects on metabolic activities in human liver microsomes
Gene polymorphisms and contents of cytochrome P450s have only limited effects on metabolic activities in human liver microsomes
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基因多态性和细胞色素P450含量对人肝微粒体代谢活动的影响有限
DOI：
10.1016/j.ejps.2016.06.015
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发表时间：
2016-09-20
影响因子：
4.6
通讯作者：
Qiao, Hailing
中科院分区：
文献类型：
--
作者：
Gao, Na;Tian, Xin;Qiao, Hailing
药代动力学的广泛个体间差异被认为是药物反应不可预测的主要原因。细胞色素P450（CYP 450）是人体肝脏中最重要的药物代谢酶，其活性的个体间差异尚不清楚。本文测定了105例正常人肝微粒体中10种CYP的代谢活性、基因多态性和蛋白质含量。结果表明，CYP 2C 19活性存在显著的个体间差异，其中最大的是CYP 2C 19活性（>600倍）。在10种CYP 2A 6、CYP 2B 6、CYP 2C 9、CYP 2D 6和CYP 3A 4/5等10个亚型和26个基因多态性位点中，只有一半对代谢活性有一定的影响，其余几乎没有影响。与野生型相比，CYP 2A 6 *1/*4基因型的Km、Vmax和克林特分别下降51.6%、88.7%和70.7%，CYP 2C 9 *1/*3基因型的Vmax和克林特分别下降32.8%和60.2%，CYP 2D 6 100 TT基因型的Km和克林特分别上升118.4%和65.2%。此外，只有4种CYP 1A 2、CYP 2A 6、CYP 2 E1和CYP 3A 5亚型的Vmax值与相应的含量呈中等或弱相关。综上所述，某些CYP基因型和含量对代谢活动的影响有限，这意味着还有其他更重要的因素影响个体间的差异。(C)2016爱思唯尔B. V.保留所有权利。
Extensive inter-individual variations in pharmacokinetics are considered as a major reason for unpredictable drug responses. As the most important drug metabolic enzymes, inter-individual variations of cytochrome P450 (CYP) activities are not clear in human liver. In this paper, metabolic activities, gene polymorphisms and protein contents of 10 CYPs were determined in 105 human normal liver microsomes. The results indicated substantial inter-individual variations in CYP activities, with the greatest being CYP2C19 activity (>600-fold). Only half of 10 CYP isoforms and 26 gene polymorphism sites had limited effects on metabolic activities, such as CYP2A6, CYP2B6, CYP2C9, CYP2D6 and CYP3A4/5, others had almost no effects. Compared with their respective wild type, K-m, V-max, and CLint decreased by 51.6%, 88.7% and 70.7% in CYP2A6*1/*4 genotype, V-max and CLint decreased by 32.8% and 60.2% in CYP2C9*1/*3 genotype, K-m increased by 118.4% and CLint decreased by 65.2% in CYP2D6 100TT genotype, respectively. Moreover, there were only 4 CYP isoforms, CYP1A2, CYP2A6, CYP2E1 and CYP3A5, which had moderate or weak correlations between Vmax values and corresponding contents. In conclusions, the genotypes and contents of some CYPs have only limited effects on metabolic activities, which imply that there are other more important factors to influence inter-individual variations. (C) 2016 Elsevier B.V. All rights reserved.