Background Chronic ethanol (EtOH) administration to experimental animals induces hepatic oxidative stress and up‐regulates mitochondrial biogenesis. The mechanisms by which chronic EtOH up‐regulates mitochondrial biogenesis have not been fully explored. In this work, we hypothesized that oxidative stress is a factor that triggers mitochondrial biogenesis after chronic EtOH feeding. If our hypothesis is correct, co‐administration of antioxidants should prevent up‐regulation of mitochondrial biogenesis genes.

Methods Rats were fed an EtOH‐containing diet intragastrically by total enteral nutrition for 150 days, in the absence or presence of the antioxidant N‐acetylcysteine (NAC) at 1.7 g/kg/d; control rats were administered isocaloric diets where carbohydrates substituted for EtOH calories.

Results EtOH administration significantly increased hepatic oxidative stress, evidenced as decreased liver total glutathione and reduced glutathione/glutathione disulfide ratio. These effects were inhibited by co‐administration of EtOH and NAC. Chronic EtOH increased the expression of mitochondrial biogenesis genes including peroxisome proliferator‐activated receptor gamma‐coactivator‐1 alpha and mitochondrial transcription factor A, and mitochondrial DNA; co‐administration of EtOH and NAC prevented these effects. Chronic EtOH administration was associated with decreased mitochondrial mass, inactivation and depletion of mitochondrial complex I and complex IV, and increased hepatic mitochondrial oxidative damage, effects that were not prevented by NAC.