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.
Keywords: AIF, apoptosis-inducing factor; AMPK, AMP-activated protein kinase; APAP, acetaminophen; ARE, antioxidant response element; ATG, autophagy-related genes; Acetaminophen hepatotoxicity; Apoptosis; Autophagy; BSO, buthionine sulfoximine; CAD, caspase-activated DNase; CYP, cytochrome P450 enzymes; DAMPs, damage-associated molecular patterns; DMSO, dimethylsulfoxide; Drug metabolism; EndoG, endonuclease G; FSP1, ferroptosis suppressing protein 1; Ferroptosis; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; Gclc, glutamate–cysteine ligase catalytic subunit; Gclm, glutamate–cysteine ligase modifier subunit; HMGB1, high mobility group box protein 1; HNE, 4-hydroxynonenal; Innate immunity; JNK, c-jun N-terminal kinase; KEAP1, Kelch-like ECH-associated protein 1; LAMP, lysosomal-associated membrane protein; LC3, light chain 3; LOOH, lipid hydroperoxides; LPO, lipid peroxidation; MAP kinase, mitogen activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MPT, mitochondrial permeability transition; Mitochondria; MnSOD, manganese superoxide dismutase; NAC, N-acetylcysteine; NAPQI, N-acetyl-p-benzoquinone imine; NF-κB, nuclear factor κB; NQO1, NAD(P)H:quinone oxidoreductase 1; NRF2; NRF2, nuclear factor erythroid 2-related factor 2; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SMAC/DIABLO, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI; TLR, toll like receptor; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; UGT, UDP-glucuronosyltransferases; mTORC1, mammalian target of rapamycin complex 1.
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