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

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Ponchaut, Sylvie Van Hoof, François [UCL] Veitch, Keith

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.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.
Publication date 1992
Journal information "Biochemical pharmacology" - Vol. 43, no. 11, p. 2435-42 (1992)
Peer reviewed yes
issn 0006-2952
Publication status Publié
Affiliation UCL
MESH Subject Animals ; Coenzyme A - metabolism ; Coenzyme A Ligases - metabolism ; Fatty Acids - metabolism ; Male ; Mitochondria, Liver - drug effects - metabolism ; Models, Chemical ; Oxygen Consumption - drug effects ; Rats ; Rats, Inbred Strains ; Repressor Proteins ; Saccharomyces cerevisiae Proteins ; Valproic Acid - analogs & derivatives - metabolism - pharmacology
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Bibliographic reference Ponchaut, Sylvie ; Van Hoof, François ; Veitch, Keith. In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions.. In: Biochemical pharmacology, Vol. 43, no. 11, p. 2435-42 (1992)
Permanent URL http://hdl.handle.net/2078.1/24665