Evaluation of the Role of Acetaldehyde in the Actions of Ethanol on Gluconeogenesis by Comparison with the Effects of Crotonol and Crotonaldehyde

Liver cells from fasted rats oxidized ethanol and crotonol at identical rates. Ethanol and crotonol increased the cytosolic lactate/pyruvate ratio to the same extent, however only ethanol increased the mitochondrial B‐hydroxybutyrate/acetoacetate ratio. The rate of oxidation of crotonaldehyde by liver cells was 30% to 50% of the rate of oxidation of acetaldehyde. Cyanam‐ide, which is especially inhibitory towards the low Km mitochondrial aldehyde dehydrogenase, inhibited the oxidation of acetaldehyde to a greater extent than it inhibited the oxidation of crotonaldehyde. Acetaldehyde, but not crotonaldehyde, increased the B‐hydrox‐ybutyrate/acetoacetate ratio; both aldehydes produced some increase in the lactate/pyruvate ratio. Consequently, differences between the effects of ethanol and crotonol on the mitochondrial redox state may relate to differences between the metabolism of their respective aldehydes. Intact mitochondria oxidized crotonaldehyde at about 10% the rate found with acetaldehyde. In deox‐ychoiate‐disrupted mitochondria, in the presence of external NAD+, crotonaldehyde was oxidized at rates less than one‐fourth the rate found with acetaldehyde. Cyanamide inhibited the oxidation of acetaldehyde to a greater extent than the oxidation of crotonaldehyde. These results suggest that crotonaldehyde is a poor substrate for the low Km mitochondrial aldehyde dehydrogenase. In isolated hepatocytes, acetaldehyde stimulated glucose production from pyruvate, but inhibited gluconeogenesis from glycerol, xylitol, and sorbitol. Crotonaldehyde had no effect on glucose production from these substrates, indicating that the effects of acetaldehyde were due to the metabolism of acetaldehyde in the mitochondria. Ethanol stimulated glucose production from pyruvate, whereas crotonol was without effect. The stimulation by ethanol, and the lack of effect by crotonol, appears to be due to changes in the mitochondrial redox state produced as a consequence of the further oxidation of acetaldehyde, but not crotonaldehyde. Crotonol and ethanol inhibited glucose production from glycerol, xylitol, and sorbitol, suggesting that changes in the cytosolic redox state play the major role in the effect of the alcohols on glucose production from these substrates. However, the inhibition by ethanol was consistently 10% to 15% greater than the inhibition by crotonol, suggesting that acetaldehyde contributes to the effects of ethanol. These differences between ethanol and crotonol are consistent with a role for acetaldehyde metabolism in the actions of ethanol. Crotonol may be a useful aid in determining the mechanism whereby ethanol alters henatic functions.