title: Green-tea polyphenols downregulate cyclooxygenase and Bcl-2 activity in acetaminophen-induced hepatotoxicity.
abstract: Acetaminophen (APAP) elicits hepatotoxicity via multifactorial pathways, including increased apoptosis, cyclooxygenase (Cox-2) generation, reactive metabolite release, and glutathione (GSH) depletion. We previously showed that mice that consumed different antioxidants in their diets were protected against APAP-induced hepatotoxicity. We therefore further investigated the mechanisms by which green-tea polyphenols (GrTP) protect against APAP-induced hepatic damage. Mice were administered a diet supplemented with GrTP or vehicle for 5 consecutive days followed by intraperitoneal (IP) injection of a toxic dose of APAP or sham. APAP administration upregulated Cox-2 and B-cell lymphoma-2 (Bcl-2) production and had an effect, albeit minor, on Cox-1 and Fas expression in hepatic tissue. GrTP supplementation normalized APAP induced Cox-2 expression and Bcl-2 activation (P < 0.01), as evidenced by immunohistochemistry and Western blot analyses. Similarly, APAP administration elicited marked depletion (99%) in hepatic reduced GSH (rGSH) and endogenous S-adenosylmethionine (SAMe) concentrations (twofold) when compared with sham. APAP also caused severe centrilobular apoptosis and necrosis accompanied by leukocyte infiltration and marked elevations in the hepatic enzyme, alanine aminotransferase (ALT) released from damaged hepatocytes, and cytokine tumor necrosis factor alpha (TNF-alpha). GrTP improved hepatic histopathology (P < 0.01) and attenuated ALT activity (P < 0.05) and the depletion of rGSH (P < 0.05). In conclusion, GrTP supplementation attenuated hepatotoxicity by normalizing Cox-2 and Bcl-2 activation, suggesting a potential use for GrTP in treatng APAP toxicity.
authors: Department of Internal Medicine, University of Kentucky Medical Center, Lexington, KY 40536, USA. helieh.oz@uky.edu
authors: Helieh S
authors: HS
authors: Oz
authors: Theresa S
authors: TS
authors: Chen
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010636:Phenols / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D059808:Polyphenols; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013662:Tea / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005419:Flavonoids; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D019253:Proto-Oncogene Proteins c-bcl-2; D013662:Tea; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000410:Alanine Transaminase; D005978:Glutathione