The effects of 2[5(4-chlorophenyl)pentyl]oxirane-2-carbonyl-Co-A on mitochondrial oxidations.
2[5(4-Chlorophenyl)pentyl]oxirane-2-carbonyl-CoA (POCA-CoA) was prepared 2[a5(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 (microM) 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 beta-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, Diabetologia 22, 456 (1982)].
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D004041:Dietary Fats / Q000008:administration & dosage; D004852:Epoxy Compounds / Q000378:metabolism* / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D011048:Polarography; D051381:Rats; D011919:Rats, Inbred Strains; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid
D000214:Acyl Coenzyme A; D004041:Dietary Fats; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D007004:Hypoglycemic Agents; D013386:Succinates; D010171:Palmitoyl Coenzyme A; C040542:S-(2-(5-(4-chlorophenyl)pentyl)oxiranecarboxylate)-coenzyme A; C033891:ethyl 2-(5-(4-chlorophenyl)pentyl)oxiran-2-carboxylate; D019802:Succinic Acid; D002334:Carnitine O-Palmitoyltransferase