Mechanism for selective perivenular hepatotoxicity of ethanol.
Chronic alcohol administration to baboons results in perivenular lesions in the liver. To study possible mechanisms, the effect of ethanol on splanchnic oxygen consumption was measured. Acute ethanol administration increased splanchnic oxygen consumption in the control baboons, but the consequences of this effect on oxygenation of the perivenular zones were offset by a concomitant rise in blood flow, resulting in unchanged hepatic venous oxygen tensions. In alcohol-fed baboons, splanchnic oxygen consumption was not increased, either in the withdrawal state or after ethanol infusion. To study the magnitude of the shift in redox state induced by ethanol in the perivenular zones, we compared the effects of ethanol on the lactate/pyruvate ratio in hepatic venous blood (an approximation of that in perivenular hepatocytes) with the ratio in total liver. Prior to ethanol infusion, the lactate and pyruvate were the same in liver and in hepatic venous blood. By contrast, in all baboons, ethanol produced a much greater rise in the lactate/pyruvate ratio and decreased pyruvate more in hepatic venous blood than in total liver. Moreover, in isolated rat hepatocytes, the ethanol-induced redox shift was markedly exaggerated by oxygen tensions similar to those found in centrolobular zones. This suggests that the normally low oxygen tensions existing in perivenular zones exaggerate the ethanol-induced redox shift, a change which may contribute to the exacerbation of the damage in the perivenular area of the hepatic lobule.
D000428:Alcohol Drinking; D000818:Animals; D000431:Ethanol / Q000097:blood; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D006503:Hepatic Veins / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects*; D010215:Papio; D014699:Venules / Q000187:drug effects / Q000473:pathology
D000431:Ethanol; D010100:Oxygen