Department of Pharmacology and Toxicology and Institute for Integrative Toxicology, Michigan State University , East Lansing, MI, USA.
Expert Opin Drug Metab Toxicol. 2020 Jun;16(6):475-491. doi: 10.1080/17425255.2020.1760246. Epub 2020 May 4.
Idiosyncratic, drug-induced liver injury (IDILI) continues to plague patients and restrict the use of drugs that are pharmacologically effective. Mechanisms of IDILI are incompletely understood, and a better understanding would reduce speculation and could help to identify safer drug candidates preclinically. Animal models have the potential to enhance knowledge of mechanisms of IDILI.
Numerous hypotheses have emerged to explain IDILI pathogenesis, many of which center on the roles of the innate and/or adaptive immune systems. Animal models based on these hypotheses are reviewed in the context of their contributions to understanding of IDILI and their limitations.
Animal models of IDILI based on an activated adaptive immune system have to date failed to reproduce major liver injury that is of most concern clinically. The only models that have so far resulted in pronounced liver injury are based on the multiple determinant hypothesis or the inflammatory stress hypothesis. The liver pathogenesis in IDILI animal models involves various leukocytes and immune mediators such as cytokines. Insights from animal models are changing the way we view IDILI pathogenesis and are leading to better approaches to preclinical prediction of IDILI potential of new drug candidates.
特发性、药物诱导的肝损伤（IDILI）持续困扰着患者，并限制了具有药理作用的药物的使用。IDILI 的机制尚不完全清楚，更好地了解这些机制可以减少猜测，并有助于在临床前阶段识别更安全的药物候选物。动物模型有可能增强对 IDILI 机制的认识。
已经出现了许多解释 IDILI 发病机制的假说，其中许多假说都集中在先天和/或适应性免疫系统的作用上。本文根据这些假说，对基于这些假说的动物模型进行了综述，探讨了它们对 IDILI 理解的贡献及其局限性。
基于激活的适应性免疫系统的 IDILI 动物模型迄今为止未能复制临床上最令人关注的主要肝损伤。迄今为止，唯一导致明显肝损伤的模型是基于多决定因素假说或炎症应激假说。IDILI 动物模型中的肝脏发病机制涉及各种白细胞和免疫介质，如细胞因子。动物模型的研究结果正在改变我们对 IDILI 发病机制的看法，并为新药候选物的 IDILI 潜在风险的临床前预测提供了更好的方法。
