This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, Z. Articles by Kang, Y. J. Search for Related Content PubMed PubMed Citation Articles by Zhou, Z. Articles by Kang, Y. J.

(American Journal of Pathology. 2002;160:2267-2274.)
© 2002 American Society for Investigative Pathology

Regular Articles

Metallothionein-Independent Zinc Protection from Alcoholic Liver Injury

Zhanxiang Zhou^*, Xiuhua Sun^*, Jason C. Lambert, Jack T. Saari and Y. James Kang^*

From the Departments of Medicine^*and Pharmacology and Toxicology,University of Louisville School of Medicine, Louisville, Kentucky; the Jewish Hospital Heart and Lung Institute,Louisville, Kentucky; and the USDA Agricultural Research Service Human Nutrition Research Center,Grand Forks, North Dakota

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 under physiological conditions and releases zinc under oxidative stress and zinc is an antioxidant element, it is likely that zinc mediates the protective action of MT. The present study was undertaken to determine the distinct role of zinc in hepatic protection from alcoholic injury. MT I/II-knockout (MT-KO) mice along with their wild-type controls were treated with three gastric doses of ethanol at 5 g/kg at 12-hour intervals. Zinc 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 zinc concentrations in MT-KO mice were lower than in wild-type mice. Zinc treatment significantly elevated hepatic MT concentrations only in wild-type mice and increased zinc concentrations in both MT-KO and wild-type mice. Ethanol treatment caused degenerative morphological changes and necrotic appearance in the livers of MT-KO mice. Microvesicular steatosis was the only ethanol-induced change in the liver of wild-type mice. Ethanol treatment decreased hepatic glutathione concentrations and increased hepatic lipid peroxidation, and the concentrations of lipid peroxide products in the wild-type mice were lower than in the MT-KO mice. All of these alcohol-induced toxic responses were significantly suppressed by zinc treatment in both MT-KO and wild-type mouse livers. These results demonstrate that zinc, independent of MT, plays an important role in protection from alcoholic liver injury. However, MT is required to maintain high levels of zinc in the liver, suggesting that the protective action of MT in the liver is likely mediated by zinc.

This article has been cited by other articles:

				Z. Zhou, J. Liu, Z. Song, C. J. McClain, and Y. J. Kang Zinc Supplementation Inhibits Hepatic Apoptosis in Mice Subjected to a Long-Term Ethanol Exposure Experimental Biology and Medicine, May 1, 2008; 233(5): 540 - 548. [Abstract] [Full Text] [PDF]

				X. Kang, Z. Song, C. J. McClain, Y. J. Kang, and Z. Zhou Zinc Supplementation Enhances Hepatic Regeneration by Preserving Hepatocyte Nuclear Factor-4{alpha} in Mice Subjected to Long-Term Ethanol Administration Am. J. Pathol., April 1, 2008; 172(4): 916 - 925. [Abstract] [Full Text] [PDF]

				Z. Zhou, X. Kang, Y. Jiang, Z. Song, W. Feng, C. J. McClain, and Y. J. Kang Preservation of Hepatocyte Nuclear Factor-4{alpha} Is Associated with Zinc Protection Against TNF-{alpha} Hepatotoxicity in Mice Experimental Biology and Medicine, May 1, 2007; 232(5): 622 - 628. [Abstract] [Full Text] [PDF]

				Y. J. Kang Metallothionein redox cycle and function. Experimental Biology and Medicine, October 1, 2006; 231(9): 1459 - 1467. [Abstract] [Full Text] [PDF]

				K. Shankar, M. Hidestrand, X. Liu, R. Xiao, C. M. Skinner, F. A. Simmen, T. M. Badger, and M. J. J. Ronis Physiologic and Genomic Analyses of Nutrition-Ethanol Interactions During Gestation: Implications for Fetal Ethanol Toxicity Experimental Biology and Medicine, September 1, 2006; 231(8): 1379 - 1397. [Abstract] [Full Text] [PDF]

				Z. Zhou, L. Wang, Z. Song, J. T. Saari, C. J. McClain, and Y. J. Kang Zinc Supplementation Prevents Alcoholic Liver Injury in Mice through Attenuation of Oxidative Stress Am. J. Pathol., June 1, 2005; 166(6): 1681 - 1690. [Abstract] [Full Text] [PDF]

				K. Tomita, T. Azuma, N. Kitamura, G. Tamiya, S. Ando, H. Nagata, S. Kato, S. Inokuchi, T. Nishimura, H. Ishii, et al. Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein Am J Physiol Gastrointest Liver Physiol, November 1, 2004; 287(5): G1078 - G1085. [Abstract] [Full Text] [PDF]

				J. C. Lambert, Z. Zhou, L. Wang, Z. Song, C. J. McClain, and Y. J. Kang Preservation of Intestinal Structural Integrity by Zinc Is Independent of Metallothionein in Alcohol-Intoxicated Mice Am. J. Pathol., June 1, 2004; 164(6): 1959 - 1966. [Abstract] [Full Text] [PDF]

				Z. Zhou, L. Wang, Z. Song, J. T. Saari, C. J. McClain, and Y. J. Kang Abrogation of Nuclear Factor-{kappa}B Activation Is Involved in Zinc Inhibition of Lipopolysaccharide-Induced Tumor Necrosis Factor-{alpha} Production and Liver Injury Am. J. Pathol., May 1, 2004; 164(5): 1547 - 1556. [Abstract] [Full Text] [PDF]

				Z. Zhou, L. Wang, Z. Song, J. C. Lambert, C. J. McClain, and Y. J. Kang A Critical Involvement of Oxidative Stress in Acute Alcohol-Induced Hepatic TNF-{alpha} Production Am. J. Pathol., September 1, 2003; 163(3): 1137 - 1146. [Abstract] [Full Text] [PDF]

				J. C. Lambert, Z. Zhou, L. Wang, Z. Song, C. J. Mcclain, and Y. J. Kang Prevention of Alterations in Intestinal Permeability Is Involved in Zinc Inhibition of Acute Ethanol-Induced Liver Damage in Mice J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 880 - 886. [Abstract] [Full Text] [PDF]