Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology
Journal Title: Journal of Clinical and Translational Research - Year 2017, Vol 3, Issue 1
Abstract
Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and mechanisms of liver injury induced by APAP overdose have been the focus of extensive investigation. Studies in the mouse model, which closely reproduces the human condition, have shown that hepatotoxicity is initiated by formation of a reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which depletes cellular glutathione and forms protein adducts on mitochondrial proteins. This leads to mitochondrial oxidative and nitrosative stress, accompanied by activation of c-jun N-terminal kinase (JNK) and its translocation to the mitochondria. This then amplifies the mitochondrial oxidant stress, resulting in translocation of Bax and dynamin related protein 1 (Drp1) to the mitochondria, which induces mitochondrial fission, and ultimately induction of the mitochondrial membrane permeability transition (MPT). The induction of MPT triggers release of intermembrane proteins such as apoptosis inducing factor (AIF) and endonuclease G into the cytosol and their translocation to the nucleus, causing nuclear DNA fragmentation and activation of regulated necrosis. Though these cascades of events were primarily identified in the mouse model, studies on human hepatocytes and analysis of circulating biomarkers from patients after APAP overdose, indicate that a number of mechanistic events are identical in mice and humans. Circulating biomarkers also seem to be useful in predicting the course of liver injury after APAP overdose in humans and hold promise for significant clinical use in the near future. Relevance for patients: This review focuses on the mechanisms behind APAP-induced hepatotoxicity and the relevance of these to the human pathophysiology. Current investigations on various biomarkers which may be useful in clinical management of APAP overdose patients are also discussed.
Authors and Affiliations
Anup Ramachandran, Hartmut Jaeschke
Keywords
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