Action of clofibrate and its analogs in rats. Dissociation of hypolipidemic effects and the induction of peroxisomal beta-oxidation.
Experiments were conducted to compare directly the effects of clofibrate (ethyl 2-(p-chlorophenoxy)isobutyrate) and its analogs on serum lipids and on the rate-limiting enzyme of the hepatic peroxisomal beta-oxidation pathway, fatty acyl-coenzyme A oxidase. Clofibrate feeding (5 g/kg diet) led to 8-10-fold increases in enzyme activity in 7 days. The enzyme remained elevated during the 28-day course of the experiment. The treatment did not lead to a lowering of serum cholesterol or triacylglycerol at any time during the experiment. In separate experiments rats were given clofibrate or one of five analogs by gastric intubation for 4 consecutive days. Four of the five analogs studied caused a significant lowering of serum triacylglycerol to about 50% of pretreatment level; another analog and clofibrate itself did not significantly affect serum triacylglycerol levels. None of the five analogs caused an induction of hepatic fatty acyl-CoA oxidase, while clofibrate treatment led to a 3-4-fold increase in enzyme activity. The results demonstrate a complete dissociation between the hypolipidemic action of these compounds and the induction of peroxisomal beta-oxidation. Thus it appears that the two phenomena are mechanistically unrelated.
D042962:Acyl-CoA Oxidase; D000818:Animals; D002784:Cholesterol / Q000097:blood; D002994:Clofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004790:Enzyme Induction; D008099:Liver / Q000201:enzymology*; D008297:Male; D008830:Microbodies / Q000201:enzymology*; D010088:Oxidoreductases / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
D014280:Triglycerides; D002784:Cholesterol; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D002994:Clofibrate