Zonal redox changes as a cause of selective perivenular hepatotoxicity of alcohol.
Alcohol-induced lesions predominate in perivenular zones of the liver. To test the hypothesis that ethanol aggravates hypoxia in this zone by stimulating oxygen consumption, we measured hepatic venous pO2 after ethanol-administration to both alcohol-fed baboons (with perivenular lesions) and their controls, and found no changes: the stimulation of oxygen consumption was fully offset by a parallel increase in blood flow. Despite the lack of hypoxia, ethanol increased lactate/pyruvate (L/P) 15-fold in hepatic venous blood and only 3-fold in liver tissue. Addition of lactate to increase arterial L/P several-fold produced no changes in the hepatic venous ratio, indicating that the equilibrium between this ratio and the cytosolic redox state was reached in one passage through the liver. Thus, the higher L/P in hepatic venous blood most likely reflects an enhanced redox shift in perivenular zones. In isolated hepatocytes, a pO2 comparable to that normally prevailing in perivenular zones mimicked the exaggeration of the ethanol-induced redox shift and aggravated inhibition of protein synthesis. We therefore propose an alternate mechanism for the selective perivenular injury; namely, that the low pO2 normally prevailing at this site aggravates the redox-linked toxicity of ethanol.
D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D005235:Fatty Liver, Alcoholic / Q000378:metabolism; D006503:Hepatic Veins / Q000187:drug effects*; D006801:Humans; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects*; D010215:Papio; D011506:Proteins / Q000378:metabolism; D011773:Pyruvates / Q000097:blood; D019289:Pyruvic Acid
D007773:Lactates; D011506:Proteins; D011773:Pyruvates; D019344:Lactic Acid; D000431:Ethanol; D019289:Pyruvic Acid; D010100:Oxygen