Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

• 作者: Hartmut Jaeschke Olamide B.Adelusi Jephte Y.Akakpo Nga T.Nguyen Giselle Sanchez-Guerrero David S.Umbaugh Wen-Xing Ding Anup Ramachandran
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（12）
• 所属期刊栏目: Reviews
• 页码范围: 3740-3755
• 页数: 16页
• 语种: 英文

摘要

Acetaminophen(APAP)is a widely used analgesic and antipyretic drug,which is safe at ther-apeutic 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 po-tential therapeutic interventions.However,the complexity of the model requires a thorough understand-ing 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 mech-anisms 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.