title: Carnitine effects on coenzyme A profiles in rat liver with hypoglycin inhibition of multiple dehydrogenases.
abstract: 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.
authors.affiliation: Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 19104, USA.
authors.forename: Y K
authors.initials: YK
authors.lastname: Lieu
authors.forename: B Y
authors.initials: BY
authors.lastname: Hsu
authors.forename: W A
authors.initials: WA
authors.lastname: Price
authors.forename: B E
authors.initials: BE
authors.lastname: Corkey
authors.forename: C A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000494:pharmacology*; D003065:Coenzyme A / Q000378:metabolism*; D003521:Cyclopropanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007005:Hypoglycins / Q000494:pharmacology*; D007659:Ketones / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000494:pharmacology
chemical_list: D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D007005:Hypoglycins; D007659:Ketones; D013141:Spiro Compounds; C071537:spiropentaneacetic acid; C041757:hypoglycin; C013122:methylenecyclopropylacetic acid; D044944:Acyl-CoA Dehydrogenases; D002331:Carnitine; D003065:Coenzyme A