Studies on the mechanism of action of the hypoglycemic agent, 2-(3-methylcinnamylhydraznoo)-propionate (BM 42.304)

Abstract

A new hypoglycemie agent, 2-(3-methylcinnamylhydrazono)-propionate MCHP (BM 42.304) was shown to be an inhibitor of the transfer of long-chain fatty acids across the mitochondrial inner membrane. The following data support this conclusion: the drug, at already 5 μM, inhibited ketogenesis from oleate but not from octanoate in the perfused guinea-pig liver; likewise, ketogenesis from l-(−)-palmitoylcarnitine and palmitoyl-CoA + l-(−)-carnitine, but not from octanoate, was depressed in isolated guinea-pig liver mitochondria. Oxigraphic measurements of the oxygen uptake by isolated mitochondria showed that the drug impaired oxygen uptake with the long-chain fatty acid derivatives but not with octanoate. Finally, in vivo effects of the drug such as hypoketonemia and an increased concentration of free fatty acids in blood are in agreement with the above formulated mechanism of action. A comment is given on the relationships between fatty acid oxidation and gluconeogenesis in the guinea-pig liver.