title: In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions.
abstract: The inhibitory effects of valproate (VPA) and nine of its metabolites on mitochondrial oxidations have been investigated. Valproate, 4-ene-VPE, 2,4-diene-VPA and 2-propylglutaric acid inhibited the rate of oxygen consumption by rat liver mitochondrial fractions with long- and medium-chain fatty acids, glutamate (+/- malate), succinate, alpha-ketoglutarate (+ malate) and pyruvate (+ malate) as substrates. Sequestration of intramitochondrial free CoA by valproate and these three metabolites has been demonstrated and quantified. However, CoA trapping could not account for all the inhibitions observed. 2-ene-VPA and 3-oxo-VPA, metabolites formed during the beta-oxidation of valproate, were not capable of trapping intramitochondrial CoA although they were inhibitors of the beta-oxidation of decanoate, probably by inhibition of the medium-chain acyl-CoA synthetase.
authors.affiliation: Laboratory of Physiological Chemistry, Catholic University of Louvain, Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Ponchaut
authors.forename: F
authors.initials: F
authors.lastname: van Hoof
authors.forename: K
authors.initials: K
authors.lastname: Veitch
mesh_terms: D000818:Animals; D003065:Coenzyme A / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008956:Models, Chemical; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D005227:Fatty Acids; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014635:Valproic Acid; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D003065:Coenzyme A