Diverse antioxidants protect against acetaminophen hepatotoxicity

Journal of Biochemical and Molecular ToxicologyVolume 18, Issue 6 p. 361-368 Research Article Diverse antioxidants protect against acetaminophen hepatotoxicity† Helieh S. Oz, Corresponding Author Helieh S. Oz [email protected] Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, KY 40536, USADepartment of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, KY 40536, USASearch for more papers by this authorCraig J. McClain, Craig J. McClain Medicine, Division of Digestive Health and Nutrition Pharmacology/Toxicology VA Medical Center, Louisville, KY,Search for more papers by this authorHerbert T. Nagasawa, Herbert T. Nagasawa VA Medical Center and Department of Medicinal Chemistry, University of Minnesota, MNSearch for more papers by this authorMukunda B. Ray, Mukunda B. Ray Pathology, University of Louisville Medical SchoolSearch for more papers by this authorWillem JS. de Villiers, Willem JS. de Villiers Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, KY 40536, USASearch for more papers by this authorTheresa S. Chen, Theresa S. Chen Pharmacology/ToxicologySearch for more papers by this author Helieh S. Oz, Corresponding Author Helieh S. Oz [email protected] Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, KY 40536, USADepartment of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, KY 40536, USASearch for more papers by this authorCraig J. McClain, Craig J. McClain Medicine, Division of Digestive Health and Nutrition Pharmacology/Toxicology VA Medical Center, Louisville, KY,Search for more papers by this authorHerbert T. Nagasawa, Herbert T. Nagasawa VA Medical Center and Department of Medicinal Chemistry, University of Minnesota, MNSearch for more papers by this authorMukunda B. Ray, Mukunda B. Ray Pathology, University of Louisville Medical SchoolSearch for more papers by this authorWillem JS. de Villiers, Willem JS. de Villiers Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky Medical Center, Lexington, KY 40536, USASearch for more papers by this authorTheresa S. Chen, Theresa S. Chen Pharmacology/ToxicologySearch for more papers by this author First published: 26 January 2005 https://doi.org/10.1002/jbt.20042Citations: 76 † This paper was partially presented at FASEB 2004, Washington DC, USA (FASEB J 2004,18:A998, abstract 645.4). AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract The reactive oxygen species-sensitive transcription nuclear factor-κB (NF-κB) plays a pivotal role in the development of acetaminophen (APAP) hepatotoxicity. We investigated the efficacy of a diverse series of antioxidants in preventing APAP-induced hepatotoxicity. BALB/c mice were divided into four groups and provided with antioxidants incorporated into chow as follows: (1) control diet; or diet supplemented with (2) S-adenosylmethionine (SAMe); (3) green tea polyphenols (GrTP); or (4) (RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). After 5 days on these diets, the animals were further subdivided into (A) given an IP injection with APAP (750 mg/kg), or (B) kept as untreated controls. The animals were sacrificed at 0, 4 h, and 24 h following APAP administration. PAP/vehicle induced marked decreases in hepatic reduced glutathione (GSH) levels and endogenous SAMe concentrations (46%) when compared to controls. APAP also caused severe centrilobular necrosis and marked increase in serum enzyme ALT activity (38-fold). Oral administration of antioxidants significantly attenuated the APAP-induced liver damage and depletion of hepatic GSH. There were profound increases in serum TNF-α levels at 4 h following APAP administration in nonsupplemented compared to antioxidant-treated animals, but no significant differences noted after 24 h. Serum amyloid A increased in APAP-challenged mice irrespective of antioxidant treatment. Finally, hepatic SAMe concentrations were drastically decreased 24 h following APAP administration, and these decreases were attenuated by pretreatment with antioxidants. In conclusion, these orally administered antioxidants with dissimilar properties provided protection against liver damage, supporting the potential use of antioxidant therapy in patients with APAP toxicity. This is the first report that GrTP and oral administration of PTCA and SAMe can provide protection against APAP injury in this model. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:361–368, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20042 Citing Literature Volume18, Issue6January 2005Pages 361-368 RelatedInformation