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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Prevention of Alterations in Intestinal Permeability Is Involved in Zinc Inhibition of Acute Ethanol-Induced Liver Damage in Mice

Departments of Pharmacology and Toxicology (J.C.L., C.J.M., Y.J.K.) and Medicine (Z.Z., L.W., Z.S., C.J.M., Y.J.K.), University of Louisville School of Medicine, Louisville, Kentucky; and Jewish Hospital Heart and Lung Institute, Louisville, Kentucky (Y.J.K.)

Acute ethanol exposure causes liver injury in experimental animals, and accumulating evidence suggests that a major responsible factor for the pathogenesis is endotoxemia, which results from bacterial endotoxin leakage from the small intestine due to increased intestinal permeability under alcohol challenge. The purpose of this study was to examine whether zinc pretreatment would inhibit acute ethanol-induced liver injury through prevention of intestinal permeability changes. Male 129 Sv^PCJ mice were treated with three intragastric doses of ZnSO₄ at 5 mg of zinc ion per kg each dosing prior to acute ethanol challenge with a single oral dose of 6 g/kg ethanol. The zinc treatment did not alter the elevation of serum concentrations of alcohol. The acute ethanol exposure caused an elevation in serum alanine aminotransferase levels as well as fatty liver and hepatic degenerative necrotic foci as determined by biochemical assay and histochemical analysis, respectively. A significant increase in liver tumor necrosis factor- (TNF-) levels was detected by enzyme-linked immunosorbent assay. These pathological effects correlated well with increases in serum endotoxin levels. Importantly, acute ethanol treatment caused significant damage to the small intestine as determined by morphological analysis of intestinal sections and permeability assay. These alcohol-induced hepatic pathological changes and TNF- elevation were significantly inhibited in the zinc-pretreated animals. The inhibitory action of zinc on alcohol-induced liver damage and activation of inflammation was associated with zinc suppression of alcohol-induced intestinal permeability changes. These results thus demonstrate that zinc prevention of increased intestinal permeability is importantly involved in the inhibition of acute ethanol-induced liver damage in mice.

Address correspondence to: Dr. Y. James Kang, Department of Medicine, University of Louisville School of Medicine, 511 S. Floyd St., MDR 530, Louisville, KY 40202. E-mail: yjkang01{at}athena.louisville.edu

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