Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
Drug Metab Dispos. 2024 Jul 16;52(8):712-721. doi: 10.1124/dmd.123.001279.
Acetaminophen (APAP) is an analgesic and antipyretic drug used worldwide, which is safe at therapeutic doses. However, an overdose can induce liver injury and even liver failure. Mechanistic studies in mice beginning with the seminal papers published by B.B. Brodie's group in the 1970s have resulted in important insight into the pathophysiology. Although the metabolic activation of APAP with generation of a reactive metabolite, glutathione depletion, and protein adduct formation are critical initiating events, more recently, mitochondria have come into focus as an important target and decision point of cell death. This review provides a comprehensive overview of the induction of mitochondrial superoxide and peroxynitrite formation and its propagation through a mitogen-activated protein kinase cascade, the mitochondrial permeability transition pore opening caused by iron-catalyzed protein nitration, and the mitochondria-dependent nuclear DNA fragmentation. In addition, the role of adaptive mechanisms that can modulate the pathophysiology, including autophagy, mitophagy, nuclear erythroid 2 p45-related factor 2 activation, and mitochondrial biogenesis, are discussed. Importantly, it is outlined how the mechanisms elucidated in mice translate to human hepatocytes and APAP overdose patients, and how this mechanistic insight explains the mechanism of action of the clinically approved antidote -acetylcysteine and led to the recent discovery of a novel compound, fomepizole, which is currently under clinical development. SIGNIFICANCE STATEMENT: Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in western countries. Extensive mechanistic research over the last several decades has revealed a central role of mitochondria in the pathophysiology of APAP hepatotoxicity. This review article provides a comprehensive discussion of a) mitochondrial protein adducts and oxidative/nitrosative stress, b) mitochondria-regulated nuclear DNA fragmentation, c) adaptive mechanisms to APAP-induced cellular stress, d) translation of cell death mechanisms to overdose patients, and e) mechanism-based antidotes against APAP-induced liver injury.
对乙酰氨基酚（APAP）是一种在世界范围内使用的镇痛和解热药物，在治疗剂量下是安全的。然而，过量使用会导致肝损伤甚至肝衰竭。自 20 世纪 70 年代 B.B.布罗迪（B.B. Brodie）小组发表的开创性论文以来，对小鼠的机制研究使人们对其病理生理学有了重要的认识。虽然 APAP 的代谢激活生成了一种反应性代谢物、谷胱甘肽耗竭和蛋白质加合物的形成是关键的起始事件，但最近，线粒体作为细胞死亡的一个重要靶点和决策点引起了人们的关注。这篇综述提供了一个全面的概述，介绍了线粒体超氧化物和过氧亚硝酸盐形成的诱导作用及其通过丝裂原激活蛋白激酶级联的传播，铁催化的蛋白质硝化引起的线粒体通透性转换孔的开放，以及依赖线粒体的核 DNA 片段化。此外，还讨论了可以调节病理生理学的适应性机制，包括自噬、线粒体自噬、核红细胞 2 p45 相关因子 2 的激活和线粒体生物发生。重要的是，概述了在小鼠中阐明的机制如何转化为人类肝细胞和 APAP 过量患者，以及这种机制上的认识如何解释临床批准的解毒剂——乙酰半胱氨酸的作用机制，并导致了一种新型化合物——非那佐辛的最近发现，目前正在临床开发中。意义：对乙酰氨基酚（APAP）诱导的肝损伤是西方国家急性肝衰竭最常见的原因。过去几十年的广泛机制研究表明，线粒体在 APAP 肝毒性的病理生理学中起核心作用。这篇综述文章全面讨论了 a）线粒体蛋白质加合物和氧化/硝化应激，b）线粒体调节的核 DNA 片段化，c）对 APAP 诱导的细胞应激的适应性机制，d）细胞死亡机制向过量患者的转化，以及 e）基于机制的解毒剂治疗 APAP 诱导的肝损伤。
