TaconicArtemis GmbH, Neurather Ring 1, Koeln, Germany.
Drug Metab Rev. 2013 Feb;45(1):110-21. doi: 10.3109/03602532.2012.738687. Epub 2012 Nov 23.
The nuclear receptors pregnane X receptor, constitutive androstane receptor, and peroxisome proliferator-activated receptor alpha have important endogenous functions and are also involved in the induction of drug-metabolizing enzymes and transporters in response to exogenous xenobiotics. Though not belonging to the same protein family, the Per-Sim-ARNT domain receptor aryl hydrocarbon receptor functionally overlaps with the three nuclear receptors in many aspects and is therefore included in this review. Significant species differences in ligand affinity and biological responses as a result of activation of these receptors have been described. Several xenobiotic receptor humanized mice have been created to overcome these species differences and to provide in vivo models that are more predictive for human responses. This review provides an overview of the different xenobiotic receptor humanized mouse models described to date and will summarize how these models can be applied in basic research and improve drug discovery and development. Some of the key applications in the evaluation of drug induction, drug-drug interactions, nongenotoxic carcinogenicity, other toxicity, or efficacy studies are described. We also discuss relevant considerations in the interpretation of such data and potential future directions for the use of xenobiotic receptor humanized mice.
核受体孕烷 X 受体、组成型雄烷受体和过氧化物酶体增殖物激活受体 α 具有重要的内源性功能，它们也参与了对外源异生物质的药物代谢酶和转运蛋白的诱导。尽管芳烃受体不属于同一蛋白家族，但与这三个核受体在许多方面具有功能重叠，因此也包括在本综述中。由于这些受体的激活，已描述了配体亲和力和生物反应的显著种属差异。已经创建了几种外源物受体人源化小鼠来克服这些种属差异，并提供更能预测人类反应的体内模型。本综述概述了迄今为止描述的不同外源物受体人源化小鼠模型，并将总结这些模型如何应用于基础研究和改善药物发现和开发。描述了一些在药物诱导、药物相互作用、非遗传毒性致癌性、其他毒性或疗效研究中的关键应用。我们还讨论了在解释这些数据时的相关注意事项以及在外源物受体人源化小鼠使用方面的未来方向。
