Cell death in drug-induced liver injury.
Cell death in drug-induced liver injury.
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DOI：
10.1016/bs.apha.2019.01.006
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Dara, Lily
中科院分区：
文献类型：
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作者：
Iorga, Andrea;Dara, Lily
药物性肝损伤(DILI)是引起肝毒性的重要原因，临床表现多种多样，其中最严重的是急性肝功能衰竭。肝细胞死亡作为药物毒性的原因是DILI的一个特征。有多种细胞死亡子程序；其中一些，如凋亡、坏死性下垂、自噬和坏死已被广泛研究，而另一些如下垂和铁性下垂则是最近被描述的。帝力的细胞死亡模式取决于罪魁祸首的药物，因为它在很大程度上决定了伤害的机制和程度。DILI的主要细胞死亡子程序是细胞凋亡和坏死，线粒体参与是两者执行的关键。少数药物如对乙酰氨基酚(APAP)可引起直接的、剂量依赖的毒性，而大多数药物可引起特异性DILI(IDILI)。IDILI是一种不可预测的肝损伤形式，不依赖于剂量，发生在具有遗传易感性的个体中，并呈现可变的潜伏期。APAP诱导的程序性坏死已被广泛研究。然而，由于疾病的复杂和多因素的性质，导致IDILI的药物引起的细胞死亡的机制和发病机制很难阐明。IDILI中的细胞死亡可能是死亡受体介导的细胞凋亡，是先天免疫系统和适应性免疫系统激活的结果，并与其他宿主因素(如遗传、性别、年龄和免疫耐受能力)相结合。本章将综述细胞死亡的不同方式，即细胞凋亡、坏死、坏死性下垂、自噬、下垂和铁性下垂及其与DILI的相关性。
Drug-induced liver injury (DILI) is an important cause of liver toxicity which can have varying clinical presentations, the most severe of which being acute liver failure. Hepatocyte death as a cause of drug toxicity is a feature of DILI. There are multiple cell death subroutines; some, like apoptosis, necroptosis, autophagy, and necrosis have been extensively studied, while others such as pyroptosis and ferroptosis have been more recently described. The mode of cell death in DILI depends on the culprit drug, as it largely dictates the mechanism and extent of injury. The main cell death subroutines in DILI are apoptosis and necrosis, with mitochondrial involvement being pivotal for the execution of both. A few drugs such as acetaminophen (APAP) can cause direct, dose-dependent toxicity, while the majority of drugs cause idiosyncratic DILI (IDILI). IDILI is an unpredictable form of liver injury that is not dose dependent, occurs in individuals with a genetic predisposition, and presents with variable latency. APAP-induced programmed necrosis has been extensively studied. However, the mechanisms and pathogenesis of cell death from drugs causing IDILI are harder to elucidate due to the complex and multifactorial nature of the disease. Cell death in IDILI is likely death receptor-mediated apoptosis and the result of an activated innate and adaptive immune system, compounded by other host factors such as genetics, gender, age, and capacity for immune tolerance. This chapter will review the different modes of cell death, namely apoptosis, necrosis, necroptosis, autophagy, pyroptosis, and ferroptosis and their pertinence to DILI.