Influence of chronic administration of valproate on ultrastructure and enzyme content of peroxisomes in rat liver and kidney: Oxidation of valproate by liver peroxisomes

Abstract

Chronic administration to rats of the anticonvulsant drug, valproate, induced proliferation of liver peroxisomes and selectively increased the activity of the enzymes involved in β-oxidation in these organelles. In kidney cortex, only a moderate increase in enzyme activity could be recored. Valproate (1% w/w in the diet for 25 to 100 days) caused the appearance on electron micrographs of unusual tubular inclusions in the matrix of liver peroxisomes. SDS-PAGE analysis of purified peroxisomal fractions from treated rats demonstrated an increase in the content of five polypeptides; four of peroxisomal inclusions correspond to the accumulation of these polypeptides in the matrix of the organelle. An in vivo evaluation of the peroxisomal hydrogen peroxide production suggested that valproate itself or one of its metabolites is substrate for peroxisomal β-oxidation. This was confirmed by in vitro studies. Activation of valproate or its metabolites by liver acyl-CoA synthetase could be demonstrated, although it was 50 times slower than that of octanoate. This reaction further led to a small, but significant production of H 2O 2 by the action of peroxisomal acyl-CoA oxidase.