Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.
Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.
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DOI：
10.3109/03602532.2011.602688
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发表时间：
2012-02
影响因子：
5.9
通讯作者：
Ramachandran A
中科院分区：
文献类型：
--
作者：
Jaeschke H;McGill MR;Ramachandran A
肝毒性是药物开发过程中的一个严重问题，对于许多已建立的药物的使用。例如，对乙酰氨基酚过量目前是美国和英国急性肝衰竭的最常见原因。对药物性肝损伤机制的评估表明，线粒体是药物毒性的关键靶点，无论是直接还是间接通过形成反应性代谢物。这些修饰的结果通常是线粒体氧化应激和过氧亚硝酸盐的形成，这导致蛋白质和线粒体DNA的结构改变，并最终导致线粒体膜渗透性转换（MPT）孔的打开。MPT孔的形成导致线粒体膜电位的崩溃和ATP合成的停止。此外，膜间蛋白质如凋亡诱导因子和核酸内切酶G的释放及其易位到细胞核导致核DNA片段化。这些事件一起触发坏死细胞死亡。或者，从线粒体释放细胞色素c和其他促凋亡因子可以促进半胱天冬酶活化和凋亡性细胞死亡。药物毒性也可通过枯否细胞和中性粒细胞形成活性氧来诱导炎症反应。如果没有适当解毒，这些细胞外产生的氧化剂可以扩散到肝细胞中并触发线粒体功能障碍和氧化应激，然后诱导MPT和坏死细胞死亡。本文综述了氧化剂的形成和细胞的防御机制，并应用这些知识更好地了解药物肝毒性，特别是对乙酰氨基酚诱导的肝损伤的机制。
Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and eventually to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in collapse of the mitochondrial membrane potential and cessation of ATP synthesis. In addition, the release of intermembrane proteins such as apoptosis-inducing factor and endonuclease G and their translocation to the nucleus leads to nuclear DNA fragmentation. Together these events trigger necrotic cell death. Alternatively, release of cytochrome c and other pro-apoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces the MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for the cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury.