Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products.
Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products.
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DOI：
10.1016/j.fct.2012.12.063
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发表时间：
2013-05
影响因子：
4.3
通讯作者：
Ramachandran, Anup
中科院分区：
文献类型：
--
作者：
Jaeschke, Hartmut;Williams, C. David;McGill, Mitchell R.;Xie, Yuchao;Ramachandran, Anup
关键词：
药用植物的提取物，其中许多已经使用了几个世纪，越来越多地在肝毒性模型中进行测试。对乙酰氨基酚（acetaminophen，APAP）诱导的肝损伤模型是评价天然产物肝保护作用的最常用模型之一，但也偶尔使用四氯化碳、硫代乙酰胺、乙醇和内毒素等肝毒性模型。APAP过量是药物性肝损伤的临床相关模型。关键机制和信号通路，引发坏死细胞死亡和无菌炎症，进行了讨论。尽管人们对APAP诱导的肝损伤的病理生理学有了越来越多的了解，但其机制很复杂，容易被误解，特别是当测试未知的化学物质（如植物提取物）时。本文讨论了使用该模型时需要考虑的基本方面，如动物种属或体外系统的选择，信号事件的时间和剂量反应，代谢活化和蛋白加合物的形成，脂质过氧化和凋亡与坏死细胞死亡的作用，以及随后的无菌炎症反应的影响。其目标是使研究人员能够选择适当的模型和实验条件来测试天然产物，从而产生临床相关的结果，并对药理学机制进行有效的解释。
Extracts from medicinal plants, many of which have been used for centuries, are increasingly tested in models of hepatotoxicity. One of the most popular models to evaluate the hepatoprotective potential of natural products is acetaminophen (APAP)-induced liver injury, although other hepatotoxicity models such as carbon tetrachloride, thioacetamide, ethanol and endotoxin are occasionally used. APAP overdose is a clinically relevant model of drug-induced liver injury. Critical mechanisms and signaling pathways, which trigger necrotic cell death and sterile inflammation, are discussed. Although there is increasing understanding of the pathophysiology of APAP-induced liver injury, the mechanism is complex and prone to misinterpretation, especially when unknown chemicals such as plant extracts are tested. This review discusses the fundamental aspects that need to be considered when using this model, such as selection of the animal species or in vitro system, timing and dose-responses of signaling events, metabolic activation and protein adduct formation, the role of lipid peroxidation and apoptotic versus necrotic cell death, and the impact of the ensuing sterile inflammatory response. The goal is to enable researchers to select the appropriate model and experimental conditions for testing of natural products that will yield clinically relevant results and allow valid interpretations of the pharmacological mechanisms.
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影响因子：
25.7
作者：
Antoine, Daniel J.;Jenkins, Rosalind E.;Dear, James W.;Williams, Dominic P.;McGill, Mitchell R.;Sharpe, Matthew R.;Craig, Darren G.;Simpson, Kenneth J.;Jaeschke, Hartmut;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
5.7
作者：
Antoine, Daniel James;Williams, Dominic P.;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
3.8
作者：
Bajt, ML;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
13.5
作者：
Bourdi, M;Masubuchi, Y;Pohl, LR
通讯作者：
Pohl, LR
影响因子：
3.6
作者：
Adams, ML;Pierce, RH;Bruschi, SA
通讯作者：
Bruschi, SA