Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of N-acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.

中文翻译：

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对乙酰氨基酚肝毒性：理解药物性肝损伤机制的范例


对乙酰氨基酚 （APAP） 过量是西方国家临床上最相关的药物肝毒性，并且由于动物模型的转化相关性，APAP 在机制上是研究最多的药物。本综述涵盖了细胞内信号转导事件，从药物代谢开始，以及涉及氧化应激和过氧亚硝酸盐的线粒体功能障碍的核心作用。线粒体衍生的核酸内切酶触发核 DNA 片段化，这是细胞死亡的不归路。此外，还讨论了限制细胞死亡的适应性机制，包括自噬、线粒体形态变化和生物发生。大量证据支持渗透性坏死是细胞死亡的方式;然而，与 Apoptosis、Ferroroptosis和 pyroptisis 的信号转导事件部分重叠是有争议讨论的基础。此外，还提供了 Kupffer 细胞、单核细胞衍生的巨噬细胞和中性粒细胞激活损伤和修复中无菌炎症的最新信息。了解这些细胞死亡机制导致发现 N-乙酰半胱氨酸和最近的氟吡唑作为对抗 APAP 毒性的有效解毒剂。