INHIBITION OF GLUCONEOGENESIS IN ISOLATED RAT-LIVER CELLS BY METHYLENECYCLOPROPYLPYRUVATE (KETOHYPOGLYCIN)

In isolated rat liver cells, hypoglycin is a less effective inhibitor of gluconeogenesis than its transamination product, methylenecyclopropylpyruvate (ketohypoglycin). Methylenecyclopropylpyruvate at 0.3 mM inhibits gluconeogenesis from all substrates tested, except fructose. Methylenecyclopropylpyruvate does not affect 14CO2 release from [1-14C]palmitate, but, in the absence of lactate, inhibits ketogenesis and causes a decrease in the [β-hydroxybutyrate]/[acetoacetate] ratio. These effects are masked with lactate (10 mM) is present. In the presence of lactate and palmitate, 0.3 mM-methylenecyclopropylpyruvate produces a fall in total acid-soluble CoA and a relative increase in short-chain acyl-CoA at the expense of CoA and acetyl-CoA without changing the ATP, ADP and aspartate contents or the [lactate]/pyruvate] ratio. Many of the effects of methylenecyclopropylpyruvate observed are consistent with inhibition of butyryl-CoA dehydrogenase and of specific CoA-dependent enzymes involved in gluconeogenesis.