Inhibition of mitochondrial carnitine palmitoyl transferase A in vivo with methyl 2-tetradecylglycidate (methyl palmoxirate) and its relationship to ketonemia and glycemia

Abstract

The oral hypoglycemic agent, methyl 2-tetradecylglycidate (Me-TDGA), which inhibits in vitro mitochondrial carnitine palmitoyl transferase A (CPT-A) was used to study the relationship of CPT inhibition to changes in ketonemia and glycemia in normal and diabetic rats. After oral administration of Me-TDGA, the CPT activity of isolated rat liver mitochondria was substantially reduced with only the presumed outer enzyme fraction CPT-A released by digitonin treatment showing reduced activity. Mitochondrial fatty acyl-CoA synthetase was not inhibited. Oral doses of 0.1-2.5 mg/kg Me-TDGA produced both a dose-dependent lowering of plasma ketones and an inhibition of liver CPT. With single doses in excess of 2.5 mg/kg, po, heart and skeletal muscle CPT were also consistently inhibited. The effect on the liver enzyme persisted for at least 48 hr following 1 mg/kg, po, while the effect on ketones disappeared by 36 hr. The degree of inhibition of liver CPT produced by Me-TDGA was not altered by diabetes or the dietary state. At low doses (0.05-0.25 mg/kg, po), the most sensitive parameter was inhibition of hepatic CPT. Both plasma ketones and CPT were lowered with doses 10-fold less (0.1 mg/kg) than were required for blood glucose lowering, thus making Me-TDGA the most potent hypoketonemic compound known. In conclusion, inhibition of liver beta-oxidation at the stage of CPT-A by Me-TDGA can explain the potent hypoketonemic effects of this compound in fasted normal and diabetic rats. Higher acute doses are needed for both inhibition of muscle CPT and lowering of blood glucose.