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, α-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 (β-oxidation of valproate, were not capable of trapping intramitochondrial CoA although they were inhibitors of the β-oxidation of decanoate, probably by inhibition of the medium-chain acyl-CoA synthetase.
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