In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions.

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.