Increased oxidative damage to mitochondrial DNA following chronic ethanol consumption.

Ethanol consumption adversely affects the structural and functional integrity of hepatic mitochondria. Some of these effects may arise from the increased cellular levels of oxidizing radicals induced by ethanol feeding. Since DNA is a potential target of free radical damage, we investigated the effect of chronic ethanol feeding on oxidative modification of mtDNA. Mitochondria were isolated from the livers of control and ethanol-fed rats and the mtDNA analyzed for the presence of 8-hydroxydeoxyguanosine (8-OHdG). A 21% increase in the level of 8-OHdG was detected in mtDNA from animals that had been fed an ethanol-containing diet for 42-76 days (control, 3.98 +/- 0.5; ethanol, 4.8 +/- 0.9 8-OHdG/100,000dG). This difference increased to 43% in animals that had been fed ethanol for 105-164 days (control, 6.9 +/- 1.0; ethanol, 9.9 +/- 1.1 8-OHdG/100,000dG). This increase in mtDNA oxidation was accompanied by a decrease in the recovery of mtDNA (42-76 days: control, 88 +/- 11; ethanol 76 +/- 8 ng/mg mitochondrial protein; 105-164 days: control, 88 +/- 13; ethanol 62 +/- 14 ng/mg mitochondrial protein). The data presented demonstrate that chronic ethanol feeding leads to increased oxidative damage of hepatic mtDNA. This may in turn result in progressive mtDNA mutations and deletions and impaired mitochondrial function.