Skip to main content
ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #163066
Title: ZINC SUPPLEMENTATION PREVENTS ALCOHOLIC LIVER INJURY IN MICE THROUGH ATTENUATION OF OXIDATIVE STRESS

Author
item ZHOU, ZHANXIANG - UNIV OF LOUISVILLE
item WANG, LIPENG - 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: 3/11/2005
Publication Date: 6/1/2005
Citation: Zhou, A., Wang, L., Song, Z., Saari, J.T., McClain, C.J., Kang, Y.J. 2005. Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress. American Journal of Pathology. 166(6):1681-1690.

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. Excess alcohol also causes zinc depletion in the liver. Prior studies in laboratory animals have shown that zinc supplementation can protect the liver against damage by alcohol, in part by inhibiting action of free radicals. Although this protection has been associated with elevation of an antioxidant protein, metallothionein, recent studies have shown that zinc can protect against alcoholic liver injury independently of metallothionein. The purpose of this study was to determine whether this protective action of zinc is caused by effects on specific enzymes associated with alcohol metabolism. We confirmed that zinc supplementation inhibited alcoholic liver damage, as assessed by a variety of indicators, and reduced changes related to oxidative stress. Further, two zinc-dependent alcohol-metabolizing enzymes were found to be reduced by alcohol intake, thus shifting alcohol metabolism to an enzyme that causes oxidative stress. These changes were also inhibited by zinc supplementation and, as for prior findings, were found to be independent of metallothionien. These findings suggest a mechanism for the benefits of zinc supplementation and strengthen the possibility that zinc treatment may have therapeutic potential for alcoholic liver damage.

Technical Abstract: Zinc depletion in the liver has been well documented in alcoholic liver disease; however, its contribution to the pathogenesis has not been fully understood. This study was undertaken to examine whether a long-term supplementation with zinc can lead to hepatic protecton from alcoholic liver injury. Metallothionein-knockout (MT-KO) and wild-type 129/Sv (WT) mice were fed a liquid alcohol diet for 12 weeks. Zinc supplementation significantly inhibited alcohol-induced hepatic zinc depletion and liver injury as measured by plasma alanine transferase activity and histopathological and ultrastructural changes in both MT-KO and WT mice, indicating an MT-independent zinc protection. Zinc also inhibited superoxide accumulation as indicated by ethidine fluorescence and the consequent oxidative molecular alterations assessed by 4-hydroxynonenal, malondialdehyde, and protein carbonyl in the liver. Alcohol-induced mitochondrial glutathione depletion was also prevented by zinc supplementation. Importantly, zinc inhibited alcohol-elevated cytochrome P450 2E1 (CYP2E1) activity, but increased the activity of alcohol dehydrogenase (ADH), without affecting chronic alcohol exposure-elevated alcohol elimination rate. These results indicate that zinc depletion is related to the altered alcohol metabolic pathway: a shift from ADH to CYP2E1 leading to oxidative injury in the liver. Zinc supplementation replenished hepatic zinc independent of MT and prevented the alteration in alcohol metabolism, resulting in suppression of oxidative injury.