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APAP诱导的肝损伤中的线粒体自噬
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Abstract:
药物性肝损伤是我国非感染性肝病中的第二大类别，也是美国肝衰竭和肝移植的主要原因。从机理上讲，药物性肝损伤可分为直接型(即剂量依赖型、内在型和可预测型)、特异型(大多数与剂量无关、特异型和不可预测型)两种主要类型。在临床前研究中，大多数药物引发的非特异性肝毒性通常会被及时发现，因此不会进一步用于临床应用，然而，有一个例外情况，那就是对乙酰氨基酚(扑热息痛，APAP)在正常治疗剂量下，这种药物是安全可靠的，但一旦超过建议用量，可能会对肝脏造成严重的危害，甚至有可能引发急性肝衰竭。在正确使用下，它对患者的健康有积极的影响，但滥用或过量使用则可能带来可怕的后果，特别是对肝脏健康的影响。在发达国家如欧美，过量服用APAP是引发急性肝衰竭的主要因素。氧化应激是APAP诱导的肝脏致病性中一个关键的起始事件，线粒体自噬已被证明可促进生存并在抗氧化反应中发挥关键作用。因此，深入探讨APAP所引发的肝损害机制，以及线粒体自噬在对乙酰氨基酚诱导的肝损害中的保护机制，有助于有针对性地开发用于干预肝损伤进程的治疗目标和计划。
Drug-induced liver injury is the second largest category of non-infectious liver disease in China, and it is also the main cause of liver failure and liver transplantation in the United States. In terms of mechanism, drug-induced liver injury can be divided into two main types: direct type (dose-dependent, intrinsic and predictable) and specific type (mostly dose-independent, specific and unpredictable). In preclinical studies, non-specific hepatotoxicity caused by most drugs is usually detected in time, so it will not be further used in clinical applications. However, there is an exception that acetaminophen (APAP) is safe and reliable at normal therapeutic doses, but once it exceeds the recommended dose, it may cause serious harm to the liver and may even cause acute liver failure. When used correctly, it has a positive impact on the health of patients, but abuse or overuse may have dire consequences, especially on liver health. In developed countries such as Europe and the United States, excessive use of APAP is the main factor leading to acute liver failure. Oxidative stress is a key initial event in APAP-induced liver pathogenicity, and mitophagy has been shown to promote survival and play a key role in the antioxidant response. Therefore, in-depth study of the mechanism of liver damage caused by APAP and the protective mechanism of mitophagy in acetaminophen-induced liver damage will help to develop therapeutic targets and plans for intervening in the process of liver injury.
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