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Valproate inhibits the mitochondrial pyruvate‐driven oxidative phosphorylation in vitro
Author(s) -
Silva M. F. B.,
Ruiter J. P. N.,
IJlst L.,
Jakobs C.,
Duran M.,
Almeida I. Tavares,
Wanders R. J. A.
Publication year - 1997
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1023/a:1005398516208
Subject(s) - biochemistry , university hospital , medicine , family medicine
Valproic acid (2-n-propylpentanoic acid; VPA), a medium-chain branched fatty acid, has proved to be an effective antiepileptic drug. It has also been used widely in the symptomatic treatment of children for a variety of types of seizure. Hepatotoxicity is one of the adverse effects. Several groups have studied the in vitr o deleterious effects of VPA on cellular intermediary metabolism. However, the exact mechanisms of VPA-associate d hepatotoxicity are still unknown. Despite the structural simplicity of valproate, its metabolic profile is quite complex. Glucuronidation and β-oxidation are quantitatively the most important routes of biotransformation, generating a complex pattern of intermediates (Baillie 1992) which could potentially interfere with mitochondrial metabolism at different levels. In the past, several papers have described inhibitory effects of VPA and its metabolites on mitochondrial oxidative phosphorylation, both in vitr o (Haas et al 1981; Becker and Harris 1983; Ponchaut et al 1992) and in vivo (Rumbach et al 1983). However, the results are not easily comparable and the reported data are quite contradictory. Although our primary interest was the effect of VPA on β-oxidation, we decided to study in parallel the interference of VPA with mitochondrial substrate oxidations. W e therefore investigated the effect of this drug on mitochondrial oxidative phosphorylation, in concentrations similar to those found in man during therapy. The effects of two of its unsaturated metabolites, 2-propyl-2-pentenoic acid (1mmol/L) ( Δ 2(E) -VPA; mitochondrial β-oxidation intermediate) and 2-propyl-4-pentenoic acid (1mmol/L) ( Δ 4 -VPA; microsomal dehydrogenation product), were also studied. Two experimental approaches were used for this study: digitonin-permeabilized rat hepatocytes for the study of the rate of ATP synthesis, and rat liver mitochondria for the study of oxygen consumption by polarography, both in the presence of selected respiratory chain substrates.