Iorga Andrea, Dara Lily
Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States; Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States; Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Adv Pharmacol. 2019;85:31-74. doi: 10.1016/bs.apha.2019.01.006. Epub 2019 Feb 20.
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.
药物性肝损伤（DILI）是肝毒性的一个重要原因，其临床表现各异，最严重的情况是急性肝衰竭。肝细胞死亡作为药物毒性的一个原因，是DILI的一个特征。存在多种细胞死亡子程序；其中一些，如凋亡、坏死性凋亡、自噬和坏死，已得到广泛研究，而其他一些，如焦亡和铁死亡，则是最近才被描述的。DILI中的细胞死亡模式取决于致病药物，因为它在很大程度上决定了损伤的机制和程度。DILI中的主要细胞死亡子程序是凋亡和坏死，线粒体参与对两者的执行都至关重要。少数药物，如对乙酰氨基酚（APAP），可导致直接的、剂量依赖性毒性，而大多数药物会引起特异质性DILI（IDILI）。IDILI是一种不可预测的肝损伤形式，不依赖剂量，发生在有遗传易感性的个体中，且潜伏期可变。APAP诱导的程序性坏死已得到广泛研究。然而，由于该疾病的复杂性和多因素性质，导致IDILI的药物引起的细胞死亡机制和发病机制更难阐明。IDILI中的细胞死亡可能是死亡受体介导的凋亡，是先天性和适应性免疫系统激活的结果，再加上其他宿主因素，如遗传、性别、年龄和免疫耐受能力。本章将综述细胞死亡的不同模式，即凋亡、坏死、坏死性凋亡、自噬、焦亡和铁死亡及其与DILI的相关性。
