Molecular Pharmacology, Vol 12, 156-166, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Pathways Responsible for the Adaptive Increase in Ethanol Utilization Following Chronic Treatment with Ethanol: Inhibitor Studies with the Hemoglobin-Free Perfused Rat Liver

¹ Johnson Research Foundation, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19174

The perfused rat liver was chosen as a model to study the metabolism of the adaptive increase in ethanol metabolism resulting from chronic treatment with ethanol. This model allows for the continuous monitoring of intracellular pigments nondestructively (pyridine nucleotide and flavoprotein fluorescence; catalase-H₂O₂ absorption), which are qualitative monitors of the alcohol dehydrogenase and catalase pathways in the liver cell. The specificity of 4-methylpyrazole for alcohol dehydrogenase and of aminotriazole for catalase has been verified in this model with these techniques. Ethanol metabolism was activated 60% over controls as a result of chronic treatment with ethanol. Rates in both groups were nearly completely abolished (less than 16 µmoles/g/hr) by 4-methylpyrazole. Similar inhibition was observed with inhibitors of the mitochondrial respiratory chain (rotenone and antimycin A) and atractyloside, an inhibitor of adenine nucleotide translocase. The adaptive increase was completely abolished with ouabain, an inhibitor of the sodium-plus potassium-activated ATPase. Basal respiratory rates (127 µmoles/g/hr) were markedly elevated (205 µmoles/g/hr) as a result of treatment with ethanol. However, succinate-dependent respiration of isolated mitochondria was either unaffected or slightly depressed in livers from ethanol-treated animals. A direct relationship between oxygen uptake and ethanol oxidation in the perfused liver was observed. The data are consistent with the hypothesis that the primary event in enhanced ethanol metabolism following chronic treatment with ethanol is an increase in ATPase activity, most likely due to the sodium pump. The ADP produced from enhanced ion movement enters the mitochondrial space and stimulates electron transport and oxygen uptake. As a consequence of these events, a greater rate of NADH reoxidation occurs, resulting in a greater rate of production of NAD⁺, which stimulates ethanol oxidation via alcohol dehydrogenase.

This article has been cited by other articles:

				J. Lemasters, S Ji, and R. Thurman Centrilobular injury following hypoxia in isolated, perfused rat liver Science, August 7, 1981; 213(4508): 661 - 663. [Abstract] [PDF]