title: Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress.
abstract: Alcoholic liver disease is associated with zinc decrease in the liver. Therefore, we examined whether dietary zinc supplementation could provide protection from alcoholic liver injury. Metallothionein-knockout and wild-type 129/Sv mice were pair-fed an ethanol-containing liquid diet for 12 weeks, and the effects of zinc supplementation on ethanol-induced liver injury were analyzed. Zinc supplementation attenuated ethanol-induced hepatic zinc depletion and liver injury as measured by histopathological and ultrastructural changes, serum alanine transferase activity, and hepatic tumor necrosis factor-alpha in both metallothionein-knockout and wild-type mice, indicating a metallothionein-independent zinc protection. Zinc supplementation inhibited accumulation of reactive oxygen species, as indicated by dihydroethidium fluorescence, and the consequent oxidative damage, as assessed by immunohistochemical detection of 4-hydroxynonenal and nitrotyrosine and quantitative analysis of malondialdehyde and protein carbonyl in the liver. Zinc supplementation suppressed ethanol-elevated cytochrome P450 2E1 activity but increased the activity of alcohol dehydrogenase in the liver, without affecting the rate of blood ethanol elimination. Zinc supplementation also prevented ethanol-induced decreases in glutathione concentration and glutathione peroxidase activity and increased glutathione reductase activity in the liver. In conclusion, zinc supplementation prevents alcoholic liver injury in an metallothionein-independent manner by inhibiting the generation of reactive oxygen species (P450 2E1) and enhancing the activity of antioxidant pathways.
authors.affiliation: University of Louisville School of Medicine, Department of Medicine, 511 South Floyd St., MDR 529, Louisville, KY 40292, USA. z0zhou01@louisville.edu
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Lipeng
authors.initials: L
authors.lastname: Wang
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
authors.forename: Jack T
authors.initials: JT
authors.lastname: Saari
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000633:toxicity; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects; D019587:Dietary Supplements; D000431:Ethanol / Q000633:toxicity; D005978:Glutathione / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000187:drug effects; D005980:Glutathione Reductase / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy*; D008668:Metallothionein / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D015032:Zinc / Q000627:therapeutic use*
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D008668:Metallothionein; D005979:Glutathione Peroxidase; D019392:Cytochrome P-450 CYP2E1; D005980:Glutathione Reductase; D005978:Glutathione; D015032:Zinc