Department of Pharmacology, Toxicology, and Therapeutic, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Pharmacology, Toxicology, and Therapeutic, University of Kansas Medical Center, Kansas City, KS, USA.
Food Chem Toxicol. 2020 Jun;140:111282. doi: 10.1016/j.fct.2020.111282. Epub 2020 Mar 21.
Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the United States and APAP-induced hepatotoxicity is initiated by formation of a reactive metabolite which depletes hepatic glutathione and forms protein adducts. Studies over the years have established the critical role of c-Jun N terminal kinase (JNK) and its mitochondrial translocation, as well as mitochondrial oxidant stress and subsequent induction of the mitochondrial permeability transition in APAP pathophysiology. However, it is now evident that mitochondrial responses to APAP overdose are more nuanced than appreciated earlier, with multiple levels of control, for example, to dose of APAP. In addition, mitochondrial dynamics, as well as the organelle's importance in recovery and regeneration after APAP-induced liver injury is also being recognized, which are exciting new areas with significant therapeutic potential. Thus, this review examines the temporal course of hepatocyte mitochondrial responses to an APAP overdose with an emphasis on mechanistic response to various trigger checkpoints such as NAPQI-mitochondrial protein adduct formation and activated JNK translocation. Mitochondrial dynamics, the organelle's role in recovery after APAP and emerging areas of research which promise to provide further insight into modulation of APAP pathophysiology by these fascinating organelles will also be discussed.
对乙酰氨基酚（APAP）过量是导致美国急性肝衰竭的主要原因，APAP 诱导的肝毒性是由活性代谢物的形成引发的，该代谢物会耗尽肝内谷胱甘肽并形成蛋白质加合物。多年来的研究已经确定了 c-Jun N 末端激酶（JNK）及其线粒体易位、线粒体氧化应激以及随后诱导的线粒体通透性转换在 APAP 病理生理学中的关键作用。然而，现在很明显，线粒体对 APAP 过量的反应比以前认为的更为复杂，存在多个控制水平，例如，APAP 的剂量。此外，线粒体动力学以及细胞器在 APAP 诱导的肝损伤后的恢复和再生中的重要性也正在得到认识，这是令人兴奋的新领域，具有重要的治疗潜力。因此，本综述检查了肝细胞线粒体对 APAP 过量的时间过程的反应，重点是对各种触发检查点的机制反应，例如 NAPQI-线粒体蛋白加合物形成和激活的 JNK 易位。线粒体动力学、细胞器在 APAP 后的恢复中的作用以及有希望为这些迷人的细胞器对 APAP 病理生理学的调节提供进一步见解的新兴研究领域也将进行讨论。
