Hartmut Jaeschke, Olamide B. Adelusi, Jephte Y. Akakpo, Nga T. Nguyen, Giselle Sanchez-Guerrero, David S. Umbaugh, Wen-Xing Ding, Anup Ramachandran. Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3740-3755

Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls
Hartmut Jaeschke, Olamide B. Adelusi, Jephte Y. Akakpo, Nga T. Nguyen, Giselle Sanchez-Guerrero, David S. Umbaugh, Wen-Xing Ding, Anup Ramachandran
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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.
Key words:    Acetaminophen hepatotoxicity    Drug metabolism    Mitochondria    Apoptosis    Ferroptosis    Autophagy    NRF2    Innate immunity   
Received: 2021-07-15     Revised: 2021-08-22
DOI: 10.1016/j.apsb.2021.09.023
Funds: Work in our laboratories was funded in part by a grant from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01 DK102142, R01 DK070195 and R01 DK125465, and National Institute of General Medicine (NIGMS) funded Liver Disease COBRE grants P20 GM103549 and P30 GM118247. J.Y.A. was supported by a NIH Predoctoral Fellowship F31 DK120194-01.
Corresponding author: Hartmut Jaeschke,
Author description:
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Hartmut Jaeschke
Olamide B. Adelusi
Jephte Y. Akakpo
Nga T. Nguyen
Giselle Sanchez-Guerrero
David S. Umbaugh
Wen-Xing Ding
Anup Ramachandran

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