The hepatic cytochrome P450 reductase null mouse as a tool to identify a successful candidate entity
The hepatic cytochrome P450 reductase null mouse as a tool to identify a successful candidate entity
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DOI：
10.1016/j.toxlet.2005.10.016
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发表时间：
2006-03-15
影响因子：
3.5
通讯作者：
Wolf, CR
中科院分区：
文献类型：
--
作者：
Henderson, CJ;Pass, GJ;Wolf, CR
细胞色素P450(CYP)在药物和外源物质的代谢中起着关键作用，多年来一直被广泛研究。许多关于肝细胞色素P450在药物代谢和处置中的作用的工作已经在体外完成，并获得了关于P450调节和功能的重要信息。然而，其他因素，如给药途径、吸收、药物转运体、肾脏清除和肝外P450，使得从体外数据到体内药代动力学的推断变得困难。已经产生了一些细胞色素P450基因敲除小鼠，尽管其中许多已经产生。由于胚胎/围产期的致死性，或在同工酶大家族中不可避免地存在功能冗余，这些同工酶的用处有限。我们已经建立了一种小鼠系(HRN)，其中细胞色素P450氧化还原酶(POR)是细胞色素P450的唯一电子供体，在肝脏中特异地缺失，导致基本上所有肝脏P450功能的丧失。HRN小鼠虽然在血脂和胆汁酸平衡方面有紊乱，但发育和繁殖正常。我们利用HRN小鼠作为一个模型来建立肝脏和肝外代谢在药物代谢和处置中的作用，并初步研究药物毒代动力学和疗效之间的关系，首先是化疗前药环磷酰胺(CPA)。(C)2005爱思唯尔爱尔兰有限公司。保留所有权利。
Cytochrome P450s (CYP) play a pivotal role in the metabolism of drugs and xenobiotics, and have been intensively Studied over many years. Much of the work carried out on the role of hepatic cytochrome P450s in drug metabolism and disposition has been done in vitro, and has yielded vital information on P450 regulation and function. However, additional factors such as route of administration, absorption, drug transporters, renal clearance and extra-hepatic P450s, make it difficult to extrapolate from in vitro data to in vivo pharmacokinetics.A number of cytochrome P450s knockout mice have been generated, although many have. been of limited usefulness due to either embryonic/perinatal lethality, or the functional redundancy inevitably found in a large family of isoenzymes. We have developed a mouse line (HRN) in which cytochrome P450 oxidoreductase (POR), the unique electron donor to cytochrome P450s is deleted specifically in the liver, resulting in the loss of essentially all hepatic P450 function. The HRN mouse, although having disturbances in lipid and bile acid homeostasis develops and breeds normally. We have used the HRN mouse as a model to establish the role of hepatic versus extra-hepatic metabolism in drug metabolism and disposition, and also to investigate the relationship between drug toxicokinetics and therapeutic effect, initially with the chemotherapeutic prodrug cyclophosphamide (CPA). (c) 2005 Elsevier Ireland Ltd. All rights reserved.