RESPONSE OF GENETICALLY-OBESE ZUCKER RATS TO CIPROFIBRATE, A HYPOLIPIDEMIC AGENT, WITH PEROXISOME PROLIFERATION ACTIVITY AS COMPARED TO ZUCKER LEAN AND SPRAGUE-DAWLEY RATS

Genetically obese Zucker (fa/fa) rats were used as an experimental mod el to study the effects of hypolipidemic agents on peroxisome prolifer ation; comparison was made with Zucker lean phenotype (Fa/ -) and Spra gue-Dawley strain/phenotype. The pharmacokinetics of a single administ ration of ciprofibrate (1 or 3 mg/kg), appeared to be similar in all s trains/phenotypes. After a 2-week oral administration at the same dosa ges, there were dosage-related increases in hepatocellular peroxisomal yield and in the hepatic enzymes' cyanide-insensitive acyl-CoA oxidas e and catalase. The peroxisomal yield was less increased in Zucker tha n in Sprague-Dawley rats, while the enzyme activities were similarly i ncreased. Although the absolute specific activity of microsomal omega- lauryl hydroxylase (cytochrome P4504A1) was lower in Zucker rats, it w as increased more in this strain than in Sprague-Dawley rats in respon se to drug exposure. The hypolipidemic effect (cholesterol and triglyc eride reduction) was more pronounced in Zucker obese rats. Based on bi ochemical and morphological results, no major differences between stra ins/phenotypes in terms of peroxisome proliferation were observed foll owing a 2-week administration of ciprofibrate.