Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat

Mitochondria are thought to play a major role in hepatic oxidative stress a ssociated with alcohol-induced liver injury. Thus, the hypothesis that deli very of the mitochondrial isoform of superoxide dismutase (Mn-SOD) via reco mbinant adenovirus would reduce alcohol-induced liver injury was tested. Ra ts were given recombinant adenovirus containing Mn-SOD (Ad.SOD2) or beta -g alactosidase (Ad.lacZ) and then fed alcohol enterally for 4 weeks. Mn-SOD e xpression and activity of Ad.SOD2 in liver mitochondria of infected animals was increased nearly 3-fold compared with Ad.lacZ-infected controls. Mitoc hondrial glutathione levels in Ad.lacZ-infected animals were decreased afte r 4 weeks of chronic ethanol, as expected, but were unchanged in Ad.SOD2-in fected animals. Alanine aminotransferase was elevated significantly by etha nol, an effect that was prevented by Ad.SOD2. Moreover, pathology (e.g. the sum of steatosis, inflammation, and necrosis) was elevated dramatically by ethanol in Ad.lacZ-treated rats. This effect was also blunted in animals i nfected with Ad.SOD2. Neutrophil infiltration was increased about 3-fold in livers from both Ad.lacZ- and Ad.SOD2-infected rats by ethanol treatment. Moreover, ESR-detectable free radical adducts in bile were increased about 8-fold by ethanol. Using C-13-labeled ethanol, it was determined that nearl y 60% of total adducts were due to the a-hydroxyethyl radical adduct. This increase in radical formation was blocked completely by Ad.SOD2 infection. Furthermore, apoptosis of hepatocytes was increased about 5-fold by ethanol , an effect also blocked by Ad.SOD2. Interestingly, tumor necrosis factor-a lpha mRNA was elevated to the same extent in both Ad.lacZ- and Ad.SOD2-infe cted animals follows ethanol exposure. These data suggest that hepatocyte m itochondrial oxidative stress is involved in alcohol-induced liver damage a nd likely follows Kupffer cell activation, cytokine production, and neutrop hil infiltration. These results also support the hypothesis that mitochondr ial oxidant production is a critical factor in parenchymal cell death cause d by alcohol.