The inhibition by valproic acid of the mitochondrial oxidation of monocarboxylic and omega-hydroxymonocarboxylic acids: possible implications for the metabolism of gamma-aminobutyric acid.
The interactions of 1-5 mM valproic acid with the hepatic fatty acid oxidation are here described. Valproic acid was not substrate for hepatic peroxisomal fatty acid oxidation. Its activation outside the mitochondrial matrix compartment was poor when compared to that of octanoic acid, a fatty acid containing the same number of carbones. Valproic acid did not inhibit the fatty acyl-CoA oxidase nor the cyanide-insensitive acyl-CoA oxidation. Valproic acid inhibited the mitochondrial oxidations of both long-chain monocarboxylyl-CoAs and omega-hydroxymonocarboxylyl-CoAs. Valproic acid prevented the oxidation by coupled mitochondria of decanoic and 10-hydroxydecanoic acids. Both butyric and 4-hydroxybutyric acids were oxidized by coupled mitochondria. These activities were abolished by preincubating the enzyme source with valproic acid. Administration to rats of 0.5% (w/w)- or 1% (w/w)-valproate containing diets were efficient in producing increased liver peroxisomal population and beta-oxidation. Preliminary investigations on the effects of valproic acid on mitochondrial fatty acid oxidation as a function of the animal used for the experiments pointed out an association of the protection of the mitochondrial process against the toxicity of the drug with enhanced carnitine acyltransferase and acyl-CoA hydrolase activities.
D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism*; D002994:Clofibrate / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002264:Carboxylic Acids; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D002994:Clofibrate