PDF(Pubmed)
Abstract：
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.
摘要：
对乙酰氨基酚（APAP）是一种广泛使用的镇痛和解热药物，在治疗剂量下是安全的，但过量服用后可能导致严重的肝损伤甚至肝衰竭。APAP肝毒性小鼠模型与人类病理生理学密切相关。因此,这种临床相关模型经常用于研究药物性肝损伤的机制,甚至用于测试潜在的治疗干预措施.然而,模型的复杂性需要对病理生理学有透彻的了解，以获得有效的结果和可转化为临床的机制信息。然而,使用此模型的许多研究都存在缺陷，这危害了科学和临床的相关性。这篇综述的目的是提供一个模型框架，在该框架中可以获得机械上合理和临床相关的数据。讨论提供了对损伤机制以及如何研究它的见解，包括药物代谢的关键作用，线粒体功能障碍，坏死细胞死亡，自噬和无菌炎症反应。此外,讨论了使用此模型时最常犯的错误。因此，在研究APAP肝毒性时考虑这些建议将有助于发现更多临床相关的干预措施.
