title: Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential.
abstract: Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death. Although immune cells can be a source of ROS in other models, no reliable evidence exists to support a role for immune cell-derived ROS in APAP hepatotoxicity. Recent studies suggest that mitochondrial targeted antioxidants can be viable therapeutic agents against hepatotoxicity induced by APAP overdose, and re-purposing existing drugs to target oxidative stress and other concurrent signaling events can be a promising strategy to increase its potential application in patients with APAP overdose.
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, USA. Electronic address: kdu@kumc.edu.
authors.forename: Kuo
authors.initials: K
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, USA. Electronic address: aramachandran@kumc.edu.
authors.forename: Anup
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, USA. Electronic address: hjaeschke@kumc.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D058492:Drug Repositioning; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D000082:Acetaminophen
keywords: Acetaminophen hepatotoxicity, mitochondria, oxidant stress; Antioxidants; Innate immunity; Lipid peroxidation; Peroxynitrite