Inhibition of medium-chain fatty acid beta-oxidation in vitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid.
Valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid, were found to inhibit strongly the metabolism of decanoic acid in homogenates of rat liver. Reductions in decanoate consumption in response to inhibitors were paralleled by decreases in the formation of octanoic and hexanoic acids, two products of decanoate beta-oxidation. In contrast, 4-pentenoic acid, an established inhibitor of long-chain fatty acid beta-oxidation, had little effect on the metabolism of decanoate. It is concluded that the title compounds are potent, broad-spectrum inhibitors of fatty acid beta-oxidation, a property which may be of key toxicological importance in the pathology of valproate-induced liver injury.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002208:Caproates / Q000378:metabolism; D002210:Caprylates / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism; D003652:Decanoic Acids / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology*
D002208:Caproates; D002210:Caprylates; D003652:Decanoic Acids; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; C037652:hexanoic acid; C045022:2-propyl-4-pentenoic acid; C031071:decanoic acid; D014635:Valproic Acid; D000255:Adenosine Triphosphate; C031492:octanoic acid; D003065:Coenzyme A