Zinc prevention and treatment of alcoholic liver disease.
Alcoholic liver disease (ALD) is associated with decreases in zinc (Zn) and its major binding protein, metallothionein (MT), in the liver. Studies using animal models have shown that Zn supplementation prevents alcohol-induced liver injury under both acute and chronic alcohol exposure conditions. There are hepatic and extrahepatic actions of Zn in the prevention of alcoholic liver injury. Zn supplementation attenuates ethanol-induced hepatic Zn depletion and suppresses ethanol-elevated cytochrome P450 2E1 (CYP2E1) activity, but increases the activity of alcohol dehydrogenase in the liver; an action that is likely responsible for Zn suppression of alcohol-induced oxidative stress. Zn also enhances glutathione-related antioxidant capacity in the liver. At the cellular level, Zn inhibits alcohol-induced hepatic apoptosis partially through suppression of the Fas/FasL-mediated pathway. Zn supplementation preserves intestinal integrity and prevents endotoxemia, leading to inhibition of endotoxin-induced tumor necrosis factor-alpha (TNF-alpha) production in the liver. Zn also directly inhibits the signaling pathway involved in endotoxin-induced TNF-alpha production. These hepatic and extrahepatic effects of Zn are independent of MT. However, low levels of MT in the liver sensitize the organ to alcohol-induced injury, and elevation of MT enhances the endogenous Zn reservoir and makes Zn available when oxidative stress is imposed. Zn has a high potential to be developed as an effective agent in the prevention and treatment of ALD.
Kang
Y James
YJ
Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA. yjkang01@louisville.edu
Zhou
Zhanxiang
Z
D000818:Animals; D017209:Apoptosis; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D019587:Dietary Supplements; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000473:pathology / Q000502:physiology; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000517:prevention & control*; D008668:Metallothionein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015032:Zinc / Q000008:administration & dosage / Q000172:deficiency / Q000627:therapeutic use*
D014409:Tumor Necrosis Factor-alpha; D008668:Metallothionein; D019392:Cytochrome P-450 CYP2E1; D015032:Zinc