对乙酰氨基酚致肝损伤的线粒体机制研究进展

Research advances in mitochondrial mechanisms of acetaminophen-induced liver injury

对乙酰氨基酚(APAP)是临床上常用的解热镇痛药物,过量使用可导致严重肝损伤。肝富含线粒体,越来越多的研究提示线粒体在APAP诱导的肝损伤中发挥重要作用。APAP诱导的肝损伤与其活性代谢产物N-乙酰基-对苯醌亚胺(NAPQI)密切相关。NAPQI可与肝线粒体蛋白共价结合,生成APAP-蛋白加合物,影响氧化还原稳态,导致线粒体结构功能障碍,最终导致肝损伤。线粒体可通过调控氧化应激、金属离子稳态、质量控制及炎症反应等多种作用机制参与APAP诱导的肝损伤。应用天然产物或化学物对线粒体损伤进行干预,可有效减轻APAP诱导的肝损伤,提示靶向调节线粒体损伤可能成为防治APAP诱导肝损伤及相关药物发现的有效策略。

Acetaminophen(APAP)is a commonly used antipyretic and analgesic drug,which can cause liver injury when used at overdose.The liver contains abundant mitochondria,which are increas⁃ingly indicated to play a critical role in APAP-induced liver injury.The liver injury induced by APAP is closely related to its active metabolite N-acetyl-p-benzoquinone imine(NAPQI).NAPQI can covalently bind to mitochondrial proteins to generate APAP-protein adducts,which influence redox balance,lead to mitochon⁃drial structural alterations and dysfunction,and consequently result in liver injury.Mitochondria can be involved in APAP-induced liver injury through various mechanisms,such as regulation of oxidative stress,metal ion homeostasis,mitochondrial quality control,and inflammatory response.The applica⁃tion of natural products/chemicals to intervene mitochondrial injury can effectively reduce APAP-induced liver injury,suggesting that targeted regulation of mitochondrial damage may provide an impor⁃tant strategy for the prevention and treatment of APAP-induced liver injury and related drug discovery.