Preservation of Intestinal Structural Integrity by Zinc Is Independent of Metallothionein in Alcohol-Intoxicated Mice

Abstract

Intestinal-derived endotoxins are importantly involved in alcohol-induced liver injury. Disruption of intestinal barrier function and endotoxemia are common features associated with liver inflammation and injury due to acute ethanol exposure. Zinc has been shown to inhibit acute alcohol-induced liver injury. This study was designed to determine the inhibitory effect of zinc on alcohol-induced endotoxemia and whether the inhibition is mediated by metallothionein (MT) or is independent of MT. MT knockout (MT-KO) mice were administered three oral doses of zinc sulfate (2.5 mg zinc ion/kg body weight) every 12 hours before being administered a single dose of ethanol (6 g/kg body weight) by gavage. Ethanol administration caused liver injury as determined by increased serum transaminases, parenchymal fat accumulation, necrotic foci, and an elevation of tumor necrosis factor (TNF-␣). Increased plasma endotoxin levels were detected in ethanol-treated animals whose small intestinal structural integrity was compromised as determined by microscopic examination. Zinc supplementation significantly inhibited acute ethanolinduced liver injury and suppressed hepatic TNF-␣ production in association with decreased circulating endotoxin levels and a significant protection of small intestine structure. As expected, MT levels remained undetectable in the MT-KO mice under the zinc treatment. These results thus demonstrate that zinc preservation of intestinal structural integrity is associated with suppression of endotoxemia and liver injury induced by acute exposure to ethanol and the zinc protection is independent of MT.

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

“…Zinc supplementation attenuated ethanol-induced increases in serum endotoxin levels, serum ALT activity, and hepatic TNF-α levels. These changes were associated with prevention of ethanol-induced liver injury (Lambert et al, 2003;Lambert et al, 2004). These results suggest that zinc brought these changes, at least in part, by preventing ethanol-induced transfer of endotoxin from intestine to circulation which could be ascribed to preservation of intestinal morphology and permeability.…”

“…In rats, chronic ethanol ingestion significantly impaired zinc absorption in the ileum, which is the most active area of zinc uptake in the intestine (Antonson and Vanderhoof, 1983). Similarly in mice, acute alcohol treatment decreased zinc concentration in the ileum (Lambert et al, 2004). Using a mouse model of acute alcohol toxicity mimicking human binge drinking (Carson and Pruett, 1996), researchers investigated whether zinc supplementation could preserve intestinal permeability that is increased by 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.…”

The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction

“…Zinc deficiency in Caco-2 cells not only induced membrane barrier damage but also increased neutrophil transmigration (16). Our previous study (29) showed that zinc protects against acute alcohol intoxication-induced intestinal histopathological changes independent of MT, suggesting the possibility that other zinc-binding proteins may mediate the effects of zinc. The present study demonstrated that zinc deprivation disassembles the tight-junction proteins, suggesting a novel mechanism of how zinc modulates the epithelial barrier.…”

Metallothionein deficiency leads to soleus muscle contractile dysfunction following acute spinal cord injury in mice

“…It is conceivable that lack of MT in the MT Ϫ/Ϫ trans animals led to greater lipid peroxidation as a result of lower cellular zinc levels. MT deficiency may compromise tissue zinc status and limit zinc availability under conditions of stress, thus leading to increased tissue damage (26). Importantly, zinc has been shown to stabilize membrane integrity and inhibit lipid peroxidation (7,8).…”