Decrease of fatty acid oxidation, ketogenesis and gluconeogenesis in isolated perfused rat liver by phenylalkyl oxirane carboxylate (B 807‐27) due to inhibition of CPT I (EC 2.3.1.21)

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Abstract
Sodium 2-[5-(4-chlorophenylpentyl]oxirane-2-carboxylate (B 807-27 or POCA) inhibits ketogenesis from endogenous and exogenous long-chain fatty acids and 14CO2 production from [U-14C]palmitate, but not from [U-14C]palmitoylcarnitine or octanoate, and inhibits gluconeogenesis from lactate and pyruvate in perfused livers of starved rats. Inhibition of ketogenesis, 14CO2 production and gluconeogenesis was complete at concentrations of 10 .mu.mol/l POCA, but onset was more rapid for inhibition of ketogenesis and CO2 production than for gluconeogenesis. Infusion of octanoate abolished inhibition of all 3 processes. Experiments with isolated rat liver mitochondria showed that carnitine palmitoyltransferase I (EC 2.3.1.21) is inhibited by POCA-CoA. The inhibitory process is dependent on time and concentration, and more pronounced in mitochondria from fed than from fasted rats. Concentrations required for 50% inhibition after 20 min preincubation with POCA-CoA are 0.02, 0.06 and 0.1 .mu.mol/l in liver mitochondria from fed, 24-h-fasted and 48-h-fasted rats, respectively. The inhibitor appears to be tightly bound to the enzyme. The extent of inhibition of carnitine palmitoyltransferase I correlates well with the hypoglycemic and hypoketonemic effects of the compounds in fasted rats. Specific inhibition of the enzyme apparently leads, due to inhibition of long-chain fatty acid utilization, to depressed ketogenesis and gluconeogenesis and; in consequence, to hypoglycemic and hypoketonemia in vivo under gluconeogenic and ketogenic conditions.