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
(1993) FEBS Letters — Vol. 322, n° 2, p. 95-100 (1993)
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- 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 DELTA4-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.
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Vamecq, J., Vallee, L., Fontaine, M., Lambert, D., Poupaert, J., & Nuyts, JP. (1993). 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. FEBS Letters, 322(2), 95-100. https://doi.org/10.1016/0014-5793(93)81545-B (Original work published 1993)