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      Liver injury induced by paracetamol and challenges associated with intentional and unintentional use

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          Abstract

          Drug induced liver injury (DILI) is a common cause of acute liver injury. Paracetamol, also known as acetaminophen, is a widely used anti-pyretic that has long been established to cause liver toxicity once above therapeutic levels. Hepatotoxicity from paracetamol overdose, whether intentional or non-intentional, is the most common cause of DILI in the United States and remains a global issue. Given the increased prevalence of combination medications in the form of pain relievers and antihistamines, paracetamol can be difficult to identify and remains a significant cause of acute hepatotoxicity, as evidenced by its contribution to over half of all acute liver failure cases in the United States. This is especially concerning given that, when co-ingested with other medications, the rise in serum paracetamol levels may be delayed past the 4-hour post-ingestion mark that is currently used to determine patients that require medical therapy. This review serves to describe the clinical and pathophysiologic features of hepatotoxicity secondary to paracetamol and provide an update on current available knowledge and treatment options.

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

          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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            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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              Acetaminophen hepatotoxicity.

              Acetaminophen is a commonly used antipyretic and analgesic agent. It is safe when taken at therapeutic doses; however, overdose can lead to serious and even fatal hepatotoxicity. The initial metabolic and biochemical events leading to toxicity have been well described, but the precise mechanism of cell injury and death is unknown. Prompt recognition of overdose, aggressive management, and administration of N-acetylcysteine can minimize hepatotoxicity and prevent liver failure and death. Liver transplantation can be lifesaving for those who develop acute liver failure.
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                Author and article information

                Contributors
                Journal
                World J Hepatol
                WJH
                World Journal of Hepatology
                Baishideng Publishing Group Inc
                1948-5182
                27 April 2020
                27 April 2020
                : 12
                : 4
                : 125-136
                Affiliations
                Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
                Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States. pyrsopni@ 123456njms.rutgers.edu
                Author notes

                Author contributions: All authors designed the study, drafted and revised the manuscript; Pyrsopoulos N supervised the study.

                Corresponding author: Nikolaos Pyrsopoulos, MD, PhD, Professor, Department of Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, University Hospital, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, United States. pyrsopni@ 123456njms.rutgers.edu

                Article
                jWJH.v12.i4.pg125
                10.4254/wjh.v12.i4.125
                7336293
                32685105
                b05e0923-be86-46a9-a6ee-5daf63736cc1
                ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                : 11 October 2019
                : 26 December 2019
                : 17 February 2020
                Categories
                Review

                paracetamol,drug-induced liver injury,hepatotoxicity,acute liver failure

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