title: N-acetylcysteine amide, a promising antidote for acetaminophen toxicity.
abstract: Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over the counter antipyretic and analgesic medications. It is safe at therapeutic doses, but its overdose can result in severe hepatotoxicity, a leading cause of drug-induced acute liver failure in the USA. Depletion of glutathione (GSH) is one of the initiating steps in APAP-induced hepatotoxicity; therefore, one strategy for restricting organ damage is to restore GSH levels by using GSH prodrugs. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an acetaminophen overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and I.V. administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteine amide (NACA), a novel antioxidant with higher bioavailability, and compared it with NAC in APAP-induced hepatotoxicity in C57BL/6 mice. Our results showed that NACA is better than NAC at a low dose (106mg/kg) in preventing oxidative stress and protecting against APAP-induced damage. NACA significantly increased GSH levels and the GSH/GSSG ratio in the liver to 66.5% and 60.5% of the control, respectively; and it reduced the level of ALT by 30%. However, at the dose used, NAC was not effective in combating the oxidative stress induced by APAP. Thus, NACA appears to be better than NAC in reducing the oxidative stress induced by APAP. It would be of great value in the health care field to develop drugs like NACA as more effective and safer options for the prevention and therapeutic intervention in APAP-induced toxicity.
authors.affiliation: Chemistry Department, Missouri University of Science and Technology, Rolla, MO 65409, USA.
authors.forename: Ahdab
authors.initials: A
authors.lastname: Khayyat
authors.affiliation: Chemistry Department, Missouri University of Science and Technology, Rolla, MO 65409, USA.
authors.forename: Shakila
authors.initials: S
authors.lastname: Tobwala
authors.affiliation: Comparative Medicine Program, Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Hart
authors.affiliation: Chemistry Department, Missouri University of Science and Technology, Rolla, MO 65409, USA. Electronic address: nercal@mst.edu.
authors.forename: Nuran
authors.initials: N
authors.lastname: Ercal
mesh_terms: D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000410:Alanine Transaminase / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D000975:Antioxidants; D000082:Acetaminophen; C487056:N-Acetylcysteinamide; D005969:Glutamate Dehydrogenase; D000410:Alanine Transaminase; D005978:Glutathione; D000111:Acetylcysteine
keywords: Acetaminophen; GSH-prodrug; Glutathione; Hepatotoxicity; NAPQI; Oxidative stress