title: Comparative evaluation of N-acetylcysteine and N-acetylcysteineamide in acetaminophen-induced hepatotoxicity in human hepatoma HepaRG cells.
abstract: Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over-the-counter antipyretic analgesic medications. Despite being safe at therapeutic doses, an accidental or intentional overdose can result in severe hepatotoxicity; a leading cause of drug-induced liver failure in the U.S. Depletion of glutathione (GSH) is implicated as an initiating event in APAP-induced toxicity. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an APAP overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and intravenous administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteineamide (NACA), a novel antioxidant, with higher bioavailability and compared it with NAC in APAP-induced hepatotoxicity in a human-relevant in vitro system, HepaRG. Our results indicated that exposure of HepaRG cells to APAP resulted in GSH depletion, reactive oxygen species (ROS) formation, increased lipid peroxidation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase release. Both NAC and NACA protected against APAP-induced hepatotoxicity by restoring GSH levels, scavenging ROS, inhibiting lipid peroxidation, and preserving mitochondrial membrane potential. However, NACA was better than NAC at combating oxidative stress and protecting against APAP-induced damage. The higher efficiency of NACA in protecting cells against APAP-induced toxicity suggests that NACA can be developed into a promising therapeutic option for treatment of an APAP overdose.
authors.affiliation: Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA.
authors.forename: Shakila
authors.initials: S
authors.lastname: Tobwala
authors.affiliation: Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA.
authors.forename: Ahdab
authors.initials: A
authors.lastname: Khayyat
authors.affiliation: Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA.
authors.forename: Weili
authors.initials: W
authors.lastname: Fan
authors.affiliation: Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA nercal@mst.edu.
authors.forename: Nuran
authors.initials: N
authors.lastname: Ercal
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000494:pharmacology; D000931:Antidotes / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D062787:Drug Overdose / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D000082:Acetaminophen; C487056:N-Acetylcysteinamide; D000111:Acetylcysteine
keywords: Glutathione-prodrug; N-acetyl-p-benzoquinoneimine; glutathione; mitochondria; oxidative stress