Mechanisms of the metabolic disturbances caused by hypoglycin and by pent-4-enoic acid in vivo studies

1. It was confirmed that administration of either hypoglycin or pent-4-enoate to rats caused severe hypoglycaemia and hypothermia. Hypothermia was prevented by keeping the animals in a thermoneutral environment (30°). Hypoglycaemia caused by hypoglycin lasted longer than that caused by pent-4-enoate. 2. Administration of hypoglycin to rats caused several volatile fatty acids to accumulate in the plasma. By contrast, the only volatile fatty acid found in plasma following administration of pent-4-enoate to rats was pent-4-enoate itself. 3. Several short-chain acyl-CoA dehydrogenase activities were irreversibly inactivated in extracts of mitochondria isolated from livers taken from rats after administration of hypoglycin; no inhibitions were found following administration of pent-4-enoate. 4. Evidence is presented that some of the branched-chain acyl-CoA esters are not, as often assumed, substrates for the butyryl-CoA dehydrogenase of β-oxidation, and that there are some specific branched-chain acyl-CoA dehydrogenases. 5. Mitochondria isolated from livers of hypoglycin-treated rats had their ability to oxidize acyl-carnitines severely impaired, and the O₂ consumption was consistent with the incomplete oxidation of the substrate as far as butyrate. Pyruvate oxidation was uninhibited in these mitochondria. 6. Mitochondria isolated from livers of pent-4-enoate-treated rats had their ability to oxidize acyl-carnitines impaired but the O₂ consumption was consistent with the complete oxidation of the substrate to acetoacetate. Pyruvate oxidation was also inhibited. During recovery, pyruvate oxidation was restored before that of palmitoyl-carnitine indicating that sequestration of mitochondrial CoASH is not the mechanism by which pent-4-enoate inhibits β-oxidation. 7. A working model is proposed to explain the in vivo effects of these compounds.