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      Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential

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          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.

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          Highlights

          • Oxidative stress plays a critical role in acetaminophen hepatotoxicity.

          • Mitochondria are the main source of ROS and RNS that are responsible for the toxicity.

          • Cytochrome P450 and inflammatory cells are probably not relevant sources of ROS for the toxicity.

          • Mitochondrial oxidative stress is a promising therapeutic target against APAP overdose.

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          Most cited references111

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          Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing

          Current drug-safety assays for hepatotoxicity rely on biomarkers with low predictive power. The production of radical species, specifically reactive oxygen species (ROS) and reactive nitrogen species (RNS), has been proposed as an early unifying event linking the bioactivation of drugs to hepatotoxicity and as a more direct and mechanistic indicator of hepatotoxic potential. Here we present a nanosensor for rapid, real-time in vivo imaging of drug-induced ROS and RNS for direct evaluation of acute hepatotoxicity. By combining fluorescence resonance energy transfer (FRET) and chemiluminescence resonance energy transfer (CRET), our semiconducting polymer–based nanosensor simultaneously and differentially detects RNS and ROS using two optically independent channels. Drug-induced hepatotoxicity and its remediation are imaged longitudinally in mice following systemic challenge with acetaminophen or isoniazid. Dose-dependent ROS and RNS activity is detected in the liver within minutes of drug challenge, preceding histological changes, protein nitration and DNA double strand break induction.
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            Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis.

            Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than 40 years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered.
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              Free radicals as mediators of tissue injury and disease.

              A radical is any molecule that contains one or more unpaired electrons. Radicals are normally generated in many metabolic pathways. Some of these radicals can exist in a free form and subsequently interact with various tissue components resulting in dysfunction. The potential role of oxygen- or xenobiotic-derived free radicals in the pathology of several human diseases has stimulated extensive research linking the toxicity of numerous xenobiotics and disease processes to a free radical mechanism. However, because free radical-mediated changes are pervasive and often poorly understood, the question of whether such species are a major cause of tissue injury and human disease remains equivocal. This review discusses cellular sources of various radical species and their reactions with vital cellular constituents. Examples of purported free radical-mediated disorders are discussed in detail to provide insights into the controversy over whether free radicals are important mediators of tissue injury.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                04 October 2016
                December 2016
                04 October 2016
                : 10
                : 148-156
                Affiliations
                [0005]Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas, USA
                Author notes
                [* ]Corresponding author. hjaeschke@ 123456kumc.edu
                Article
                S2213-2317(16)30173-2
                10.1016/j.redox.2016.10.001
                5065645
                27744120
                e0a1fb52-59cd-4ae1-84ac-1acd7dadbb78
                © 2016 Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 11 September 2016
                : 1 October 2016
                : 3 October 2016
                Categories
                Review Article

                acetaminophen hepatotoxicity, mitochondria, oxidant stress,antioxidants,lipid peroxidation,innate immunity,peroxynitrite

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