Effects of α-p-chlorophenoxyisobutyryl ethyl ester (CPIB) with and without androsterone on cholesterol biosynthesis in rat liver

Abstract

SUMMARY a-p-Chlorophenoxyisobutyrate (CPIB) or a mixture of CPIBwith a small amount of androsterone (Atromid) fed to rats at a level of 0.3% of the diet was found to increase the liver weight by about 25%, and to decrease the cholesterol concentration in liver by about 10% and in plasma by about 30%. No change in rate of growth or of food consumption was observed. The rate of cholesterol biosynthesis per gram of liver, estimated from the incorporation of acetate-l-Cl4, was decreased by about 70% in liver slices from rats fed CPIB or Atromid. Conversion of mevalonate-2-Cl4 into cholesterol was decreased only slightly. No decrease in the formation of ketone bodies from acetate-l-C14 in liver slices was found to result from CPIB, nor in the synthesis of triglyceride from acetate-1 -C14, indicating that the site of the inhibitory action of the drug is between acetyl CoA and mevalonate. CPIB is similar to dietary cholesterol in that it is not inhibitory when added to liver homogenates at concentrations up to about lop3 M. In intact rats, both CPIB and Atromid significantly decreased the rate of cholesterol synthesis per gram of liver, as measured by the incorporation of acetate-l-C14 or of tritium water, but the effect was not as large as in liver slice studies. No decrease was noted in cholesterol synthesis in intestine. Cholesterol synthesis by the whole liver was decreased less by CPIB or Atromid than when expressed per gram of liver. The decrease in acetate-C14 incorporation in liver cholesterol per 100 g of rat body weight was estimated to be about 65% by the liver slice method and about 38% in intact animals; tritium water incorporation gave a mean decrease of 22%. The differences were significant for acetate incorporation but at the borderline for tritium water.