Interaction of glycolysis and respiration in perfused rat liver. Changes in oxygen uptake following the addition of ethanol.

Abstract

The effect of ethanol on hepatic respiration and glycolysis was studied in perfused rat livers. 1. Ethanol increased the rate of oxygen uptake in livers from fed rats, but decreased the rate in livers from fasted animals perfused in the absence of added substrates. 2. Addition of ethanol decreased the rate of lactate + pyruvate production reflecting an inhibition of glycolysis irrespective of whether glycogen or added glucose was the substrate. 3. Half-maximal stimulation of respiration and inhibition of glycolysis were observed at ethanol concentrations between 0.2 and 0.4 mM. 4. A stoichiometric relationship of one mole of stimulated oxygen uptake to 3.6 mol of decreased lactate + pyruvate production was observed under a variety of experimental conditions. 5. The effects of ethanol on oxygen uptake and lactate + pyruvate production were abolished by the addition of 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, but were unaffected by aminooxyacetate, an inhibitor of hydrogen transport across the mitochondrial membrane. 6. Carboxyatractyloside, an inhibitor of adenine nucleotide translocase, largely abolished the increase in oxygen uptake due to ethnol, but had little effect on the inhibitory action of ethanol on glycolysis. These data indicate that the ethanol-stimulated oxygen uptake is due to an increased flux through the mitochondrial respiratory chain and that it involves the NAD+-dependent oxidation of ethanol by alcohol dehydrogenase. The data are consistent with the hypothesis that the ethanol-stimulated respiration results from an increased demand for mitochondrial oxidative phosphorylation as a consequence of the decreased extramitochondrial ATP generation following inhibition of glycolysis by ethanol.