title: Suppression of Fas-mediated signaling pathway is involved in zinc inhibition of ethanol-induced liver apoptosis.
abstract: Apoptosis is critically involved in hepatic pathogenesis induced by acute alcohol exposure. This study was undertaken to test the hypothesis that zinc interferes with an important Fas ligand-mediated pathway in the liver, leading to the inhibition of ethanol-induced apoptosis. Male 129/Sv(PC)J mice were injected subcutaneously with ZnSO4 (5 mg of Zn ion/kg) in 12-hr intervals for 24 hr before intragastric administration of ethanol (5 g/kg) in 12-hr intervals for 36 hr. Ethanol-induced apoptosis in the liver was detected by a terminal deoxynucleotidyl transferase nick-end labeling assay and was further confirmed by electron microscopy. The number of apoptotic cells in the livers pretreated with zinc was significantly decreased, being only 15% of that found in the animals treated with ethanol only. Characteristic apoptotic morphological changes observed by electron microscopy were also inhibited by zinc. Importantly, zinc inhibited ethanol-induced activation of caspase-3, the primary executioner protease responsible for alcohol-induced liver apoptosis, and caspase-8 as determined by enzymatic assay. Immunohistochemical analysis revealed that zinc inhibited ethanol-induced endogenous Fas ligand activation, which is a key component in signaling pathways leading to hepatic caspase-8 and subsequent caspase-3 activation and apoptosis. These results demonstrate that zinc is a potent inhibitor of acute ethanol-induced liver apoptosis, and this effect occurs primarily through zinc interference with Fas ligand pathway and the suppression of caspase-3.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Lambert
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D015398:Signal Transduction / Q000502:physiology*; D015032:Zinc / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology*
chemical_list: D019014:fas Receptor; D000431:Ethanol; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D015032:Zinc