Hepatic microbody proliferation and catalase synthesis induced by methyl clofenapate, a hypolipidemic analog of CPIB

Abstract

The effects of the administration of methyl clofenapate (methyl-2-[4-(p-chlorophenyl)phenoxy]2-methylpropionate) on the inducibility of hepatic microbody (peroxisome) proliferation and catalase synthesis were studied in male rats and in both sexes of wild type (Cs(a) strain) and acatalasemic (Cs(b) strain) mice. These investigations included electron microscopic examination of livers, assay of liver catalase activity, quantitation of catalase protein by immunotitration procedure, and measurements of serum cholesterol and glyceride-glycerol levels. In all groups of animals administration of methyl clofenapate at dietary concentrations of 0.015, 0.05 and 0.125% produced a significant and sustained increase in number of hepatic microbody (peroxisome) profiles. There was no appreciable increase in mitochondrial population, but several mitochondria were markedly enlarged and possessed numerous cristae. The hepatic microbody proliferation in male rats and in both sexes of wild type mice following methyl clofenapate administration was associated with a twofold increase in catalase activity and in the concentration of catalase protein. The increase in microbody population in acatalasemic mice, however, was not accompanied by a significant elevation of the catalase activity, which is due to the unusual heat lability of the mutant catalase enzyme. A marked decrease in serum cholesterol and glyceride-glycerol levels was observed in male rats following methyl clofenapate administration which paralleled the increase in liver catalase activity. In both strains of mice there was a significant reduction in serum glyceride-glycerol concentrations. All the above effects of methyl clofenapate were fully reversed when the drug was withdrawn from the diet of male wild type mice. The demonstration of microbody proliferation and catalase induction with hypolipidemic compounds, CPIB, nafenopin and, in these studies, with methyl clofenapate suggests a possible but as yet unclarified relationship between microbodies and hypolipidemia.