Role of the Redox State in Ethanol‐Induced Suppression of Citrate‐Cycle Flux in the Perfused Liver of Normal, Hyper‐ and Hypothyroid Rats

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Abstract
The mechanism of the ethanol‐induced suppression of the citric acid cycle has been studied by single‐passage perfusion of livers from normal, triiodothyronine‐treated and propylthiouraciltreated rats. Ethanol oxidation increased the lactate/pyruvate ratio in the perfusion medium to about 50 and depressed the 14CO2 formation from [1‐14C]acetate and [1‐14C]hexanoato (taken to reflect citrate cycle flux) by 67% and 60%, respectively, in normal livers. In the livers of the hyperthyroid animals ethanol suppressed [1‐14C]acetate oxidation by 22% and [1‐14C]hexanoate oxidation by 34%, and the lactate/pyruvate ratio was only increased to about 20. In the hypothyroid group ethanol enhanced the lactate/pyruvate ratio slightly more than in the controls and suppressed the oxidation of acetate and hexanoate by 79 and 62%, respectively. Hepatic ethanol elimination was slightly slower in the hyper‐ and hypothyroid groups than in the controls. Hexanoate (1 mM) stimulated oxygen uptake in all groups but inhibited ethanol oxidation by 45% in the hyperthyroid group and only by 18% in the hypothyroid group. Pyruvate, on the other hand, stimulated ethanol elimination only slightly in the hyperthyroid group, by about 50% in the controls and by about 70% in the hypothyroid group. Oxidation of acetate and hexanoate was also depressed by acetaldehyde. This effect was potentiated by pyrazole, which blocked the reduction of acetaldehyde and caused an increased shift in the lactate/pyruvate ratio, thus indicating that acetaldehyde also affects the citric acid cycle by causing a shift in the redox state. A highly significant correlation was observed between the effect of ethanol on the output of 14CO2 from the labelled substrates and the shift in the lactate/pyruvate ratio. Experiments with different input levels of lactate and pyruvate demonstrated that the citric acid cycle is susceptible to the fall in pyruvate resulting from the shift in the redox state during ethanol oxidation.