Barzi Mercedes, Pankowicz Francis P, Zorman Barry, Liu Xing, Legras Xavier, Yang Diane, Borowiak Malgorzata, Bissig-Choisat Beatrice, Sumazin Pavel, Li Feng, Bissig Karl-Dimiter
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX-77030, USA.
Graduate Program, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX-77030, USA.
Nat Commun. 2017 Jun 28;8(1):39. doi: 10.1038/s41467-017-00049-x.
Only one out of 10 drugs in development passes clinical trials. Many fail because experimental animal models poorly predict human xenobiotic metabolism. Human liver chimeric mice are a step forward in this regard, as the human hepatocytes in chimeric livers generate human metabolites, but the remaining murine hepatocytes contain an expanded set of P450 cytochromes that form the major class of drug-metabolizing enzymes. We therefore generated a conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene combined with Il2rg /Rag2 /Fah (PIRF) mice. Here we show that homozygous PIRF mouse livers are readily repopulated with human hepatocytes, and when the murine Por gene is deleted (<5%), they predominantly use human cytochrome metabolism. When given the anticancer drug gefitinib or the retroviral drug atazanavir, the Por-deleted humanized PIRF mice develop higher levels of the major human metabolites than current models. Humanized, murine Por-deficient PIRF mice can thus predict human drug metabolism and should be useful for preclinical drug development.Human liver chimeric mice are increasingly used for drug testing in preclinical development, but express residual murine p450 cytochromes. Here the authors generate mice lacking the Por gene in the liver, and show that human cytochrome metabolism is used following repopulation with human hepatocytes.
在研发的药物中，只有十分之一能够通过临床试验。许多药物研发失败是因为实验动物模型难以准确预测人体对外源生物的代谢情况。在这方面，人肝嵌合小鼠向前迈进了一步，因为嵌合肝脏中的人肝细胞能够产生人体代谢物，但剩余的小鼠肝细胞含有一组扩展的细胞色素P450，它们构成了主要的药物代谢酶类别。因此，我们构建了一种NADPH - P450氧化还原酶（Por）基因条件性敲除的Il2rg−/Rag2−/Fah−（PIRF）小鼠。我们在此表明，纯合PIRF小鼠的肝脏很容易被人肝细胞重新填充，当小鼠Por基因被敲除（<5%）时，它们主要利用人细胞色素进行代谢。给予抗癌药物吉非替尼或逆转录病毒药物阿扎那韦时，Por基因缺失的人源化PIRF小鼠产生的主要人体代谢物水平高于当前模型。因此，人源化、小鼠Por基因缺陷的PIRF小鼠能够预测人体药物代谢，应该对临床前药物研发有用。人肝嵌合小鼠在临床前研发中越来越多地用于药物测试，但会表达残留的小鼠细胞色素P450。本文作者构建了肝脏中缺乏Por基因的小鼠，并表明在用人肝细胞重新填充后会利用人细胞色素进行代谢。
