Gene polymorphisms and contents of cytochrome P450s have only limited effects on metabolic activities in human liver microsomes

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• 作者：Na Gao¹ ; Xin Tian¹ ; Yan Fang ; Jun Zhou ; Haifeng Zhang ; Qiang Wen ; Linjing Jia ; Jie Gao ; Bao Sun ; Jingyao Wei ; Yunfei Zhang ; Mingzhu Cui ; Hailing Qiao ; ^{qiaohl@zzu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cytochrome P450 ; Drug metabolism ; Gene polymorphism ; Protein content ; Individual variations
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：20 September 2016
• 年：2016
• 卷：92
• 期：Complete
• 页码：86-97
• 全文大小：1214 K

文摘

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 CL_int decreased by 51.6%, 88.7% and 70.7% in CYP2A6*1/*4 genotype, V_max and CL_int decreased by 32.8% and 60.2% in CYP2C9*1/*3 genotype, K_m increased by 118.4% and CL_int 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 V_max 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.