The inhibition of long-chain fatty acyl-CoA synthetase by enoximone in rat heart mitochondria.
The mechanism by which enoximone, a reported phosphodiesterase inhibitor, inhibits the oxidation of long-chain fatty acids was studied in isolated rat heart mitochondria using a series of 14C-labeled substrates. Enoximone decreased palmitate oxidation in a time- and concentration-dependent manner. Fifty percent inhibition of palmitate oxidation was achieved with 250 microM of enoximone. In contrast to its effect on palmitate, enoximone (250 microM) increased octanoate oxidation by 30%, whereas pyruvate oxidation was unaffected by enoximone. At that dose there was no effect on the oxidation of palmitoyl-CoA and palmitoyl carnitine. The degree of palmitate oxidation inhibited by enoximone was parallel to the inhibition of acyl-CoA synthetase in both rat heart mitochondria and microsomes. These results suggest that enoximone is a reversible inhibitor of long-chain fatty acyl-CoA synthetase. Moreover, the reaction, which is catalyzed by this enzyme, is a rate-limiting step in the pathway of fatty acid oxidation in rat heart mitochondria.
Abdel-aleem
S
S
Glaxo Inc. Research Institute, Department of Pharmacology, Research Triangle Park, North Carolina.
Youssef
J
J
Badr
M
M
Morgan
P
P
Frangakis
C
C
D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors*; D000818:Animals; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors*; D017335:Enoximone; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D000214:Acyl Coenzyme A; D007093:Imidazoles; D017335:Enoximone; D003066:Coenzyme A Ligases