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

Abstract

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 ethanolinduced liver injury through prevention of intestinal permeability changes. Male 129 Sv PC J mice were treated with three intragastric doses of ZnSO 4 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 alcoholinduced 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.

Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: Summary of a symposium

“…Similar results were obtained in a mice study where animals were administered 1 mg/kg bacterial LPS by intragastirc gavage one hour after administration of alcohol by gavage (Lambert et al, 2003). Ethanol alone, but not LPS alone, significantly increased plasma endotoxin level, and ethanol +LPS caused further significant increase in plasma endotoxin levels (Lambert et al, 2003). These studies clearly indicate that alcohol can increase intestinal permeability to various macromolecules including endotoxin.…”

“…Furthermore, intestinal permeability to fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4000 D (FD4) was increased by long-term ethanol administration (Tamai et al, 2002). Similar results were obtained in a mice study where animals were administered 1 mg/kg bacterial LPS by intragastirc gavage one hour after administration of alcohol by gavage (Lambert et al, 2003). Ethanol alone, but not LPS alone, significantly increased plasma endotoxin level, and ethanol +LPS caused further significant increase in plasma endotoxin levels (Lambert et al, 2003).…”

“…Similarly, administration of 20% ethanol to rats for 14 days by gavage resulted in significant mucosal disruption of ileum as evidenced by subepithelial edema of villous tips, cellular infiltration of the villi and exfoliation (Napolitano et al, 1995). In mice, acute ethanol exposure (single oral dose of 6 g/kg) caused sever injury to the mucosal lining of ileum of the small intestine (Lambert et al, 2003). This included breaches in the epithelial layer of the villi, submucosal blebbing, and ulceration of the villi (Lambert et al, 2003).…”

“…In mice, acute ethanol exposure (single oral dose of 6 g/kg) caused sever injury to the mucosal lining of ileum of the small intestine (Lambert et al, 2003). This included breaches in the epithelial layer of the villi, submucosal blebbing, and ulceration of the villi (Lambert et al, 2003). The mucosal damage caused by alcohol might result in an impaired intestinal barrier function, enabling toxins of gut-inhabiting bacteria such as endotoxins to enter the systemic circulation and to contribute to liver injury after alcohol consumption.…”

“…These findings demonstrate that ethanol increased the transfer of endogenous as well as exogenous endotoxin from the intestine to the general circulation. Increased serum endotoxin levels were associated with liver injury as detected by an elevation in serum alanine aminotransferase (ALT) activity, fatty liver and hepatic degenerative necrotic foci along with a significant increase in hepatic TNF-α levels (Lambert et al, 2003;Lambert et al, 2004). Zinc supplementation attenuated ethanol-induced increases in serum endotoxin levels, serum ALT activity, and hepatic TNF-α levels.…”