Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
Mol Pharmacol. 2011 Sep;80(3):518-28. doi: 10.1124/mol.111.071845. Epub 2011 May 31.
Cytochrome P450 (P450) 3A4 is the predominant P450 enzyme expressed in human liver and intestine, and it is involved in the metabolism of approximately 50% of clinically used drugs. Because of the differences in the multiplicity of CYP3A genes and the poor correlation of substrate specificity of CYP3A proteins between species, the extrapolation of CYP3A-mediated metabolism of a drug from animals to man is difficult. This situation is further complicated by the fact that the predictability of the clinically common drug-drug interaction of pregnane X receptor (PXR)-mediated CYP3A4 induction by animal studies is limited as a result of marked species differences in the interaction of many drugs with this receptor. Here we describe a novel multiple humanized mouse line that combines a humanization for PXR, the closely related constitutive androstane receptor, and a replacement of the mouse Cyp3a cluster with a large human genomic region carrying CYP3A4 and CYP3A7. We provide evidence that this model shows a human-like CYP3A4 induction response to different PXR activators, that it allows the ranking of these activators according to their potency to induce CYP3A4 expression in the human liver, and that it provides an experimental approach to quantitatively predict PXR/CYP3A4-mediated drug-drug interactions in humans.
细胞色素 P450（CYP）3A4 是人类肝脏和肠道中表达的主要 P450 酶，参与约 50%临床使用药物的代谢。由于 CYP3A 基因的多样性以及物种间 CYP3A 蛋白底物特异性的相关性较差，因此难以将药物的 CYP3A 介导的代谢从动物外推到人类。由于许多药物与该受体的相互作用在物种间存在明显差异，因此动物研究中预测妊娠相关 X 受体 (PXR) 介导的 CYP3A4 诱导的临床常见药物相互作用的可预测性受到限制，这种情况变得更加复杂。在这里，我们描述了一种新型的多个人源化小鼠系，该小鼠系结合了 PXR、密切相关的组成型雄烷受体的人源化以及用携带 CYP3A4 和 CYP3A7 的大片段人基因组区域替换小鼠 Cyp3a 簇。我们提供的证据表明，该模型对不同的 PXR 激活剂表现出类似于人类的 CYP3A4 诱导反应，它可以根据这些激活剂在人类肝脏中诱导 CYP3A4 表达的效力对其进行排序，并且它为定量预测人类 PXR/CYP3A4 介导的药物相互作用提供了一种实验方法。
