Enoximone inhibits hepatic mitochondrial long-chain acyl-CoA synthetase

The phosphodiesterase inhibitor, enoximone, was previously shown to cause paradoxical effects on cardiac lipid metabolism. The present study was undertaken to elucidate the effects of enoximone on the hepatic mitochondrial pathway of fatty acid oxidation. Results presented here show that in isolated rat liver mitochondria, palmitate oxidation was inhibited progressively by increasing concentrations of enoximone. Maximum inhibition (35%) of mitochondrial oxygen uptake was attained at 250 microM enoximone. At this concentration, enoximone did not affect the oxidation of either palmitoyl-CoA or palmitoyl carnitine. Also, enoximone did not inhibit the oxidation of the short-chain fatty acid, hexanoate, neither did it affect the respiratory chain in the mitochondria. These data suggest that enoximone specifically inhibits long-chain acyl-CoA synthetase activity. This was confirmed experimentally when the activity of this enzyme was determined in the absence and presence of enoximone. Discovering inhibitors of specific steps in lipid metabolism should provide a useful tool to investigate mechanisms regulating this pathway.