The effects of 2{5(4-chlorophenyl) pentyl}oxirane-2-carbonyl-CoA on mitochondrial oxidations

2{5(4-Chlorophenyl)pentyl}oxirane-2-carbonyl-CoA (POCA-CoA) was prepared from 2{5(4-chlorophenyl)pentyl}oxirane-2-carboxylate (POCA) and characterised chromatographically. POCA-CoA does not inhibit citrate cycle oxidations or effect oxidative phosphorylation by rat liver mitochondria. POCA-CoA at low (μM) concentrations, but not free POCA^?, specifically inhibits palmitoyl-CoA oxidation at the stage of carnitine palmitoyltransferase I (CPT I) situated on the outer face of the inner mitochondria membrane. Palmitoyl-carnitine oxidation was not inhibited by POCA-CoA. POCA-CoA inhibits palmitoyl-CoA oxidation in liver mitochondria from fed rats more strongly than it does in mitochondria from fasted rats, similarly to the inhibition by malonyl-CoA [E. D. Saggerson and C. A. Carpenter, FEBS Lett. 129, 225 (1981)]. Palmitoyl-CoA, by contrast with palmitoylcarnitine, is not quantitatively oxidised to acetoacetate by liver mitochondrial fractions, presumably due to competing palmitoyl-CoA hydrolase activity. In the presence of POCA-CoA the amount oxidised is decreased further because the slower rate of oxidation allows more palmitoyl-CoA to be hydrolysed to palmitate. The oxidation of palmitoyl-CoA, but not that of palmitoyl-carnitine, was strongly decreased in washed liver and muscle mitochondrial fractions from POCA-fed animals. POCA^? inhibited the oxidation of {U-¹⁴C}palmitate in cultured human fibroblasts, and caused small increases in ¹⁴CO₂ production from {1-¹⁴C}pyruvate and {U-¹⁴C}glucose. Inhibition of β-oxidation at the stage of CPT I by POCA-CoA can explain the powerful hypoketonaemic and hypoglycaemic effects of POCA in fasted normal and fasted diabetic animals [H. P. O. Wolf, K. Eistetter and G. Ludwig, Diabetologia22, 456 (1982)].