Differential regulation of manganese superoxide dismutase activity by alcohol and TNF in human hepatoma cells.
Increasing evidence implicates free radical processes in the pathogenesis of ethanol-induced liver injury. One of the antioxidant defense systems in mammalian cells is the mitochondrial enzyme manganese superoxide dismutase (MnSOD). MnSOD activity is increased by agents that cause oxidative stress. One such agent is the cytokine tumor necrosis factor-alpha (TNF). Increased serum/tissue TNF levels have been observed in alcoholic liver disease, and TNF has been postulated to play a role in ethanol-induced liver injury. Substantial evidence suggests that ethanol itself can cause oxidative stress. In order to investigate the mechanism of the cellular adaptive response to ethanol-induced oxidative stress, the effects of short-term ethanol exposure on MnSOD RNA, protein, and activity were determined in a human hepatoma cell line (HepG2). We found that exposure to ethanol (25 mM concentration) for 72 h increased the protein level and enzyme activity of MnSOD. However, examination of the mRNA levels of the enzyme showed no corresponding increase. Long-term administration of ethanol (10 weeks) did not significantly increase MnSOD protein and MnSOD activity. MnSOD activity was significantly increased by TNF. Thus it appears that both TNF and ethanol are capable of increasing MnSOD activity presumably via enhanced oxidative stress. However, unlike TNF, acute ethanol administration increases the activity of MnSOD without increasing MnSOD mRNA. The increase in MnSOD after a short-term dose of ethanol is diminished with repeated ethanol administrations. These findings are compatible with the view that chronic exposure to ethanol suppresses the cellular adaptive response to oxidative stress. If this adaptive response of MnSOD is lessened, it may have implications in the increased toxicity due to prolonged ethanol exposure.
D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D000431:Ethanol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D013482:Superoxide Dismutase