Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress.
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.
Zhou
Zhanxiang
Z
University of Louisville School of Medicine, Department of Medicine, 511 South Floyd St., MDR 529, Louisville, KY 40292, USA. z0zhou01@louisville.edu
Wang
Lipeng
L
Song
Zhenyuan
Z
Saari
Jack T
JT
McClain
Craig J
CJ
Kang
Y James
YJ
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*
D002492:Central Nervous System Depressants; D000431:Ethanol; D008668:Metallothionein; D005979:Glutathione Peroxidase; D019392:Cytochrome P-450 CYP2E1; D005980:Glutathione Reductase; D005978:Glutathione; D015032:Zinc