On the effect of the hypolipidaemic phenyl ether CH 13 437 on the liver metabolism of the rat

Abstract

The new tetrahydronaphthalene derivative 2-methyl-2- p-(1,2,3,4-tetrahydro-1-naphthyl)-phenoxy-propionic acid (CH 13 437) is a compound with a strong hypolipidaemic effect with a direct influence on the liver metabolism. In vitro inhibition occured at the stage of the acetyl-CoA carboxylase. In vivo experiments in the rat were performed in which liver enzymes of the carbohydrate and lipid metabolism and the concentrations of metabolic intermediates in the liver were determined. The compound CH 13 437, in vivo, inhibits key enzymes of gluconeogenesis (phosphoenolpyruvate carboxykinase) and those of glycolysis (pyruvate kinase, phosphofructokinase); citrate synthase shows a moderate increase in activity and malic enzyme a considerable increase paralleled by a high activity increase of the microsomal NADPH-oxidase. The activity of the citrate cleavage enzyme was reduced in refeeding experiments. The concentrations of acetyl-CoA, acetoacetate, citrate and pyruvate—due to the enzyme activity changes found—have undergone a dose-dependent increase. According to the results discussed, the findings indicate inhibition of lipogenesis and retarded glycolysis in the liver as the cause of the hypolipidaemic effect of the compound CH 13 437.