Valproic acid metabolites inhibit dihydrolipoyl dehydrogenase activity leading to impaired 2-oxoglutarate-driven oxidative phosphorylation.
The effect of the antiepileptic drug valproic acid (VPA) on mitochondrial oxidative phosphorylation (OXPHOS) was investigated in vitro. Two experimental approaches were used, in the presence of selected respiratory-chain substrates: (1) formation of ATP in digitonin permeabilized rat hepatocytes and (2) measurement of the rate of oxygen consumption by polarography in rat liver mitochondria. VPA (0.1-1.0 mM) was found to inhibit oxygen consumption and ATP synthesis under state 3 conditions with glutamate and 2-oxoglutarate as respiratory substrates. No inhibitory effect on OXPHOS was observed when succinate (plus rotenone) was used as substrate. We tested the hypothesis that dihydrolipoyl dehydrogenase (DLDH) might be a direct target of VPA, especially its acyl-CoA intermediates. Valproyl-CoA (0.5-1.0 mM) and valproyl-dephosphoCoA (0.5-1.0 mM) both inhibited the DLDH activity, acting apparently by different mechanisms. The decreased activity of DLDH induced by VPA metabolites may, at least in part, account for the impaired rate of oxygen consumption and ATP synthesis in mitochondria if 2-oxoglutarate or glutamate were used as respiratory substrates, thus limiting the flux of these substrates through the citric acid cycle.
Luís
Paula B M
PB
Centro de Patogénese Molecular, Unidade de Biologia Molecular e Biopatologia Experimental, (UBMBE) Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Ruiter
Jos P N
JP
Aires
Cátia C P
CC
Soveral
Graça
G
de Almeida
Isabel Tavares
IT
Duran
Marinus
M
Wanders
Ronald J A
RJ
Silva
Margarida F B
MF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D008058:Dihydrolipoamide Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D007656:Ketoglutaric Acids; D014635:Valproic Acid; D000255:Adenosine Triphosphate; D008058:Dihydrolipoamide Dehydrogenase; D010100:Oxygen