Molecular Pharmacology, Vol 20, 621-630, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

The Effect of Ethanol on the Activities of the Key Gluconeogenic and Glycolytic Enzymes of Rat Liver

¹ Department of Pharmacology, College of Medicine, Ohio State University, Columbus, Ohio 43210

A systematic study was conducted to determine the effects of an acute dose of ethanol (1-5 g/kg body weight) on all of the key regulatory enzymes of glucose metabolism in rat liver. The effect of ethanol on the activities of these enzymes varied depending on the dose of ethanol, whether or not the rats were fed or fasted, and whether or not the enzymes were assayed in the presence of their specific activators. In general, ethanol increased the total activities of the key gluconeogenic enzymes and decreased the total activities of the key glycolytic enzymes in the livers of fed rats. For example, ethanol increased the activities of pyruvate carboxylase and glucose 6-phosphatase and decreased the activities of glucokinase, hexokinase, phosphofructokinase, and pyruvate kinase. The extent of the inhibition of phosphofructokinase activity by ethanol was greater when this enzyme was assayed in the absence of its specific activators (70% inhibition) than when assayed in their presence (20% inhibition). Similarly, the inhibition of the activity of pyruvate kinase was greater when assayed in the absence of its activator. In fasted rats, ethanol decreased the activities of liver pyruvate carboxylase and phosphoenolpyruvate carboxykinase, and increased the activities of phosphofructokinase and pyruvate kinase. Ethanol-induced changes in glucose levels may be related to the differential effect of ethanol on these enzymes. Ethanol increased the ratio of the activities of the key gluconeogenic enzymes to glycolytic enzymes in the livers of fed animals. For example, with ethanol, 5 g/kg of body weight, the activity at the glucose 6-phosphatase/hexokinase + glucokinase step increased by 55%; at the fructose bisphosphatase/phosphofructokinase step, by 200%; and at the pyruvate carboxylase + phosphoenolpyruvate carboxykinase/ pyruvate kinase step, by 88%. In contrast, in fasted rats, ethanol decreased the activity at the fructose bisphosphatase/phosphofructokinase step by 7%, and at the pyruvate carboxylase + phosphoenolpyruvate carboxykinase/pyruvate kinase step by 41%. These results suggest that ethanol-induced hyperglycemia in fed animals may be a consequence of an increase in the ratio of the activities of the key gluconeogenic enzymes to the glycolytic enzymes. A decrease in the ratio of the activities of these enzymes may be responsible for the ethanol-induced hypoglycemia in fasted animals. Ethanol may alter the activities of these enzymes by influencing the transition of the active-inactive forms or by affecting the total content of these enzymes.

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