Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, U.K.
Biochem J. 2019 Apr 15;476(7):1149-1158. doi: 10.1042/BCJ20170780.
Adverse drug reactions (ADRs) are the unintended side effects of drugs. They are categorised as either predictable or unpredictable drug-induced injury and may be exhibited after a single or prolonged exposure to one or multiple compounds. Historically, toxicology studies rely heavily on animal models to understand and characterise the toxicity of novel compounds. However, animal models are imperfect proxies for human toxicity and there have been several high-profile cases of failure of animal models to predict human toxicity e.g. fialuridine, TGN1412 which highlight the need for improved predictive models of human toxicity. As a result, stem cell-derived models are under investigation as potential models for toxicity during early stages of drug development. Stem cells retain the genotype of the individual from which they were derived, offering the opportunity to model the reproducibility of rare phenotypes Differentiated 2D stem cell cultures have been investigated as models of hepato- and cardiotoxicity. However, insufficient maturity, particularly in the case of hepatocyte-like cells, means that their widespread use is not currently a feasible method to tackle the complex issues of off-target and often unpredictable toxicity of novel compounds. This review discusses the current state of the art for modelling clinically relevant toxicities, e.g. cardio- and hepatotoxicity, alongside the emerging need for modelling gastrointestinal toxicity and seeks to address whether stem cell technologies are a potential solution to increase the accuracy of ADR predictivity in humans.
药物不良反应（ADRs）是药物的非预期副作用。它们被分为可预测或不可预测的药物引起的损伤，并且可能在单次或多次暴露于一种或多种化合物后表现出来。从历史上看，毒理学研究严重依赖动物模型来了解和描述新型化合物的毒性。然而，动物模型并不是人类毒性的完美替代物，并且已经有一些动物模型未能预测人类毒性的高知名度案例，例如 fialuridine 和 TGN1412，这突出了需要改进人类毒性的预测模型。因此，正在研究干细胞衍生模型作为药物开发早期毒性的潜在模型。干细胞保留了它们所源自的个体的基因型，为复制罕见表型提供了机会。已经研究了分化的 2D 干细胞培养物作为肝毒性和心脏毒性的模型。然而，它们的成熟度不足，特别是在肝细胞样细胞的情况下，意味着它们的广泛使用目前并不是解决新型化合物的非靶标和经常不可预测的毒性等复杂问题的可行方法。这篇综述讨论了建模临床相关毒性（例如心脏毒性和肝脏毒性）的最新技术，以及新兴的建模胃肠道毒性的需求，并探讨了干细胞技术是否是提高人类 ADR 预测准确性的潜在解决方案。
