Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase.
Because alcoholic liver disease has been linked to oxidative stress, we investigated the effect of a compromised antioxidant defense system, Cu, Zn-superoxide dismutase (Sod1) deficiency, on alcohol-induced liver injury. C57BL/129SV wild-type (Sod1(+/+)) and Sod1 knockout (Sod1(-/-)) mice were fed dextrose or ethanol (10% of total calories) liquid diets for 3 weeks. Histologic evaluation of liver specimens of Sod1(-/-) mice fed ethanol showed the development of liver injury ranging from mild to extensive centrilobular necrosis and inflammation. Sod1(+/+) mice fed ethanol showed mild steatosis; both Sod1(+/+) and Sod1(-/-) mice fed the dextrose diet had normal histology. Alanine transaminase levels were significantly elevated only in Sod1(-/-) mice fed ethanol. Cytochrome P450 2E1 (CYP2e1) activity was elevated about 2-fold by ethanol in Sod1(+/+) and Sod1(-/-) mice. Ethanol consumption increased levels of protein carbonyls and lipid peroxidation aldehydic products in the liver of Sod1(-/-) mice. Hepatic adenosine triphosphate (ATP) content was reduced dramatically in Sod1(-/-) mice fed ethanol in association with a decrease in the mitochondrial reduced glutathione (GSH) level and activity of MnSOD. Immunohistochemical determination of 3-nitrotyrosine (3NT) residues in liver sections of the Sod1 knockout mice treated with ethanol showed a significant increase of 3NT staining in the centrilobular areas. In conclusion, a rather moderate ethanol consumption promoted oxidative stress in Sod1(-/-) mice, with increased formation of peroxynitrite, protein carbonyls, and lipid peroxidation and decreased mitochondrial GSH and MnSOD. We speculate that the increased oxidative stress causes mitochondrial damage and reduction of ATP content, leading to alcoholic liver injury. This model may be useful in further mechanistic studies on alcohol-induced liver injury.
Department of Pharmacology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Irina G
IG
Kessova
Ye-Shih
YS
Ho
Swan
S
Thung
Arthur I
AI
Cederbaum
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009566:Nitrates / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000378:metabolism
D009566:Nitrates; D011506:Proteins; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D013482:Superoxide Dismutase; D005978:Glutathione