Pyruvate uptake is inhibited by valproic acid and metabolites in mitochondrial membranes.
The pyruvate uptake rate in inverted submitochondrial vesicles prepared from rat liver was optimized and further characterized; the potential inhibitory effects of the anticonvulsive drug valproic acid or 2-n-propyl-pentanoic acid (VPA), Delta4-valproic acid or 2-n-propyl-4-pentenoic acid and the respective coenzyme A (CoA) conjugates were studied in the presence of a proton gradient. All tested VPA metabolites inhibited the pyruvate uptake, but the CoA esters were stronger inhibitors (40% and 60% inhibition, respectively, for valproyl-CoA and Delta4-valproyl-CoA, at 1mM). At the same concentration, the specific inhibitor 2-cyano-4-hydroxycinnamate decreased the pyruvate uptake rate by 70%. The reported inhibition of the mitochondrial pyruvate uptake may explain the significant impairment of the pyruvate-driven oxidative phosphorylation induced by VPA.
Aires
Cátia C P
CC
iMED.UL, Centro de Patogénese Molecular, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Soveral
Graça
G
Luís
Paula B M
PB
ten Brink
Herman J
HJ
de Almeida
Isabel Tavares
IT
Duran
Marinus
M
Wanders
Ronald J A
RJ
Silva
Margarida F B
MF
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D003065:Coenzyme A / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D019289:Pyruvic Acid / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000378:metabolism / Q000494:pharmacology*
D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; C071194:2-n-propyl-4-pentynoic acid; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid; D019289:Pyruvic Acid; D003065:Coenzyme A