The effects of 2[5(4-chlorophenyl)pentyl]oxirane-2-carbonyl-Co-A on mitochondrial oxidations

Biochem Pharmacol. 1984 Feb 1;33(3):475-81. doi: 10.1016/0006-2952(84)90243-0.

Abstract

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)].

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / pharmacology*
  • Animals
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors
  • Dietary Fats / administration & dosage
  • Epoxy Compounds / metabolism*
  • Epoxy Compounds / pharmacology
  • Ethers, Cyclic / metabolism*
  • Fibroblasts / metabolism
  • Hypoglycemic Agents / metabolism*
  • In Vitro Techniques
  • Male
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxidation-Reduction
  • Palmitoyl Coenzyme A / metabolism
  • Polarography
  • Rats
  • Rats, Inbred Strains
  • Succinates / metabolism
  • Succinic Acid

Substances

  • Acyl Coenzyme A
  • Dietary Fats
  • Epoxy Compounds
  • Ethers, Cyclic
  • Hypoglycemic Agents
  • Succinates
  • Palmitoyl Coenzyme A
  • S-(2-(5-(4-chlorophenyl)pentyl)oxiranecarboxylate)-coenzyme A
  • ethyl 2-(5-(4-chlorophenyl)pentyl)oxiran-2-carboxylate
  • Succinic Acid
  • Carnitine O-Palmitoyltransferase