Development of Mice Exhibiting Hepatic Microsomal Activity of Human CYP3A4 Comparable to That in Human Liver Microsomes by Intravenous Administration of an Adenovirus Vector Expressing Human CYP3A4
Development of Mice Exhibiting Hepatic Microsomal Activity of Human CYP3A4 Comparable to That in Human Liver Microsomes by Intravenous Administration of an Adenovirus Vector Expressing Human CYP3A4
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DOI：
10.2133/dmpk.dmpk-13-rg-109
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发表时间：
2014-08-25
影响因子：
2.1
通讯作者：
Mizuguchi, Hiroyuki
中科院分区：
文献类型：
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作者：
Kuno, Shuichi;Sakurai, Fuminori;Mizuguchi, Hiroyuki
细胞色素P450 3A 4（CYP 3A 4）在药物的药代动力学和安全性方面起着至关重要的作用。然而，由于CYP 3A 4和其他药物代谢酶的催化活性在人体和动物器官之间存在差异，因此很难使用实验动物的数据正确预测药物在人体中的药代动力学和肝毒性。为了容易地产生用于适当评价人CYP 3A 4介导的药物代谢的动物模型，我们基于我们的表现出显著较低肝毒性的新型Ad载体（Ad-E4- 122 aT-hCYP 3A 4）开发了表达人CYP 3A 4的腺病毒（Ad）载体。以2 x 1011个病毒颗粒/小鼠的剂量静脉内给予Ad-E4- 122 aT-hCYP 3A 4，产生了表现出与人肝脏中相似水平的人CYP 3A 4活性的小鼠，如使用肝微粒体的地塞米松代谢实验中所示。与接受对照Ad载体的小鼠相比，Ad-E4- 122 aT-hCYP 3A 4给药小鼠中6 β OHD的曲线下面积（AUC）高2.7倍。因此，这种表达人CYP 3A 4的Ad载体将成为评价实验动物肝脏中人CYP 3A 4介导的药物代谢的有力工具。
Cytochrome P450 3A4 (CYP3A4) plays a crucial role in the pharmacokinetic and safety profiles of drugs. However, it is difficult to properly predict the pharmacokinetics and hepatotoxicity of drugs in humans using data from experimental animals, because the catalytic activities of CYP3A4 and other drug-metabolizing enzymes differ between human and animal organs. In order to easily generate an animal model for proper evaluation of human CYP3A4-mediated drug metabolism, we developed a human CYP3A4-expressing adenovirus (Ad) vector based on our novel Ad vector exhibiting significantly lower hepatotoxicity (Ad-E4-122aT-hCYP3A4). Intravenous administration of Ad-E4-122aT-hCYP3A4 at a dose of 2 x 1011 virus particles/mouse produced a mouse exhibiting human CYP3A4 activity at a level similar to that in the human liver, as shown in the dexamethasone metabolic experiment using liver microsomes. The area under the curve (AUC) of 6 beta OHD was 2.7-fold higher in the Ad-E4-122aT-hCYP3A4-administered mice, compared with the mice receiving a control Ad vector. This Ad vector-expressing human CYP3A4 would thus be a powerful tool for evaluating human CYP3A4-mediated drug metabolism in the livers of experimental animals.