hypoglycin-a and spiropentaneacetic-acid

To examine the changes in coenzyme A profile and the possible corrective effects of carnitine supplementation in the genetic disorders of mitochondrial beta-oxidation, we carried out experiments using an inhibitor of multiple acyl-CoA dehydrogenase enzymes, methylenecyclopropaneacetic acid (MCPA), in rat hepatocytes. MCPA irreversibly inhibited ketone synthesis from straight-chain fatty acids (butyrate, octanoate, palmitate) and branched-chain fatty acids (alpha-ketoisocaproate) with a parallel 70-90% reduction of hepatocyte acetyl-CoA levels. Alone, MCPA or substrates halved free CoA levels to 15% of total CoA and doubled short- and medium-chain acyl-CoA levels to 30% of total CoA. With MCPA plus substrates combined, free CoA levels were 10% of total CoA, and short- and medium-chain acyl-CoA levels were 45% of total CoA. Comparable changes in CoA profiles were found in a patient with a severe genetic defect in beta-oxidation. Neither the suppression of ketogenesis nor the alterations in CoA profiles induced by MCPA inhibition could be corrected by carnitine supplementation.

Topics: Acyl-CoA Dehydrogenases; Animals; Carnitine; Coenzyme A; Cyclopropanes; Enzyme Inhibitors; Hypoglycins; Ketones; Lipid Metabolism, Inborn Errors; Liver; Mitochondria, Liver; Rats; Rats, Sprague-Dawley; Spiro Compounds