CoA esters of valproic acid and related metabolites are oxidized in peroxisomes through a pathway distinct from peroxisomal fatty and bile acyl-CoA beta-oxidation.
In rat liver homogenates fortified with the appropriate cofactors (ATP and CoA), valproic acid induced H2O2 production rates by far lower than those recorded on the straight medium-chain fatty acid n-octanoic acid. Using directly the CoA esters of these carboxylic acids as substrates for the rat liver H2O2-generating enzyme activities, valproyl-CoA, and n-octanoyl-CoA were found to induce similar oxidation rates. In the rat liver homogenates, cyanide-insensitive valproyl-CoA and octanoyl-CoA oxidations occurred at rates similar to those of valproyl-CoA and octanoyl-CoA oxidase(s), respectively. Studies on fractions obtained from rat liver postnuclear supernatants by isopycnic centrifugation on a linear sucrose density gradient disclose that the density distribution of valproyl-CoA oxidase superimposes to those of catalase, fatty acyl-CoA oxidase and cyanide-insensitive fatty acyl-CoA oxidation, three peroxisomal marker activities. By contrast, the cyanide-insensitive valproyl-CoA oxidation does not adopt the typical peroxisomal distribution of these activities but rather exhibits a mitochondrial localization with, however, a minor peroxisomal component. Interestingly enough, the comparative study of rat tissue distribution, inducibility by clofibrate and sensitivity to deoxycholate indicated that valproyl-CoA oxidase is an enzyme distinct from fatty acyl-CoA oxidase and bile acyl-CoA oxidase. Taken as a whole, the results presented here support the occurrence of a peroxisomal oxidation of the CoA ester of valproic acid and its delta 4-enoic derivate which might be characterized by two major features: initiation by an acyl-CoA oxidase distinct from fatty and bile acyl-CoA oxidases, and inability to complete the beta-oxidation cycle which would not proceed, at significant rates, further than the beta-hydroxyacyl-CoA dehydrogenation step in peroxisomes.
Vamecq
J
J
North France Center for the Study of Childhood Epilepsy, Hôpital B, Centre Hospitalier Régional Universitaire de Lille, France.
Vallee
L
L
Fontaine
M
M
Lambert
D
D
Poupaert
J
J
Nuyts
J P
JP
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002994:Clofibrate / Q000494:pharmacology; D004790:Enzyme Induction; D044943:Fatty Acid Desaturases / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000378:metabolism*
D000214:Acyl Coenzyme A; D001647:Bile Acids and Salts; D005227:Fatty Acids; C045335:valproyl-coenzyme A; D014635:Valproic Acid; D006861:Hydrogen Peroxide; D044943:Fatty Acid Desaturases; D002994:Clofibrate