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

Acta Pharmaceutica Sinica B

Olamide B. Adelusi¹  Giselle Sanchez-Guerrero²  Wen-Xing Ding²  Jephte Y. Akakpo²  Hartmut Jaeschke³  Anup Ramachandran⁴  Nga T. Nguyen⁴  David S. Umbaugh⁴ 

[1] Department of Pharmacology, Toxicology &Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA;Corresponding author.;;Department of Pharmacology, Toxicology &

关键词: Acetaminophen hepatotoxicity;    Drug metabolism;    Mitochondria;    Apoptosis;    Ferroptosis;    Autophagy;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown