CoA esters of valproic acid and related metabolites are oxidized in peroxisomes through a pathway distinct from peroxisomal fatty and bile acyl-CoA β-oxidation

Abstract

In rat liver homogenates fortified with the appropriate cofactors (ATP and CoA), valproic acid induced H 2O 2 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 H 2O 2-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 Δ4-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 β-oxidation cycle which would not proceed, at significant rates, further than the β-hydroxyacyl-CoA dehydrogenation step in peroxisomes.