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Title: METALLOTHIONEIN-INDEPENDENT ZINC PROTECTION FROM ALCOHOLIC LIVER INJURY

Author
item ZHOU, ZHANXIANG - UNIV OF LOUISVILLE
item SUN, XIUHUA - UNIV OF LOUISVILLE
item LAMBERT, JASON - UNIV OF LOUISVILLE
item Saari, Jack
item KANG, Y - UNIV OF LOUISVILLE

Submitted to: American Journal of Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/18/2002
Publication Date: 6/1/2002
Citation: Zhou, Z., Sun, X., Lambert, J.C., Saari, J.T., Kang, Y.J. 2002. Metallothionein-independent zinc protection from alcoholic liver injury. American Journal of Pathology. 160:2267-2274.

Interpretive Summary: Excessive intake of alcohol causes liver damage in part because oxidative metabolism of alcohol produces highly reactive molecules called free radicals that attack the liver. Prior studies in laboratory animals have shown that genetically increasing a protein called metallothionein protects the animals against the damaging effects of alcohol, including the production of free radicals. Because metallothionein is a metal binding protein that carries large amounts of zinc, we hypothesized that the protective effect of metallothionein is caused by zinc. To test this proposal, normal rats and those genetically devoid of metallothionein were pre-treated with zinc prior to receiving large amounts of alcohol. Zinc treatment was found to protect the rats against alcohol-induced liver damage, including free radical damage, in both normal and metallothionein- free rats. These findings indicate that zinc can protect against alcoholic liver damage independently of metallothionein and that prevention of alcoholic liver disease may not only benefit from stimulation of metallothionein production but by adequate, perhaps supplemental, zinc nutrition.

Technical Abstract: Previous studies using metallothionein (MT)-overexpressing transgenic mice have demonstrated that MT protects the liver from oxidative injury induced by alcohol. The mechanism of action of MT is unknown. Because MT primarily binds to zinc (Zn) under physiological conditions and it releases Zn under oxidative stress and Zn is an antioxidant element, it is likely that Zn mediates the protective action of MT. The present study was undertaken to determine the role of Zn in hepatic protection from alcoholic injury. MT I/II-knockout (MT-KO) mice along with their wild-type (WT) controls were treated with 3 gastric doses of ethanol at 5 g/kg at 12 h intervals. Zn sulfate was injected intraperitoneally in a dosage of 5 mg/kg/day for 3 days before ethanol treatment. MT concentrations in MT-KO mice were very low and Zn concentrations in MT-KO mice were lower than in WT mice. Zn treatments significantly elevated hepatic MT concentrations only in WT mice eand increased Zn concentrations in both MT-KO and WT mice. Ethanol treatment caused degenerative morphological changes and necrotic appearance in the livers of WT mice. Microvascular steatosis was the only ethanol- induced change in the livers of WT mice. Ethanol treatment decreased hepatic glutathione concentrations and increased hepatic lipid peroxidation, although the concentrations of lipid peroxide products in the WT mice were lower than in the MT-KO mice. All of these alcohol-induced toxic responses were significantly suppressed by Zn treatment in both MT-KO and WT mouse livers. These results demonstrate that Zn, independent of MT, plays an important role in protection from alcoholic liver injury. However, MT is required to maintain high levels of Zn in the liver, suggesting that mediated by Zn.