Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, is effective in the treatment of hypercholesterolemic patients and is currently being evaluated as a potential agent for dissolving gallstones. We therefore evaluated its effect on cholesterol metabolism in a rat model. A low-cholesterol diet containing 0.1% lovastatin was fed 15 h and 7 and 21 days. Microsomal HMG-CoA reductase activity, hepatic cholesterol synthesis, blood cholesterol, and biliary lipid output were determined and compared with control rats. Hepatic cholesterol synthesis increased ninefold after 7 days and levels of HMG-CoA reductase activity sevenfold. Biliary cholesterol excretion maximally increased fourfold. Biliary lipid output was still elevated after 21 days of treatment (cholesterol 3-fold and phospholipid 2-fold, P less than 0.01). Bile salt output did not change. Augmented responses to lovastatin were present but less on the high-cholesterol diet. The data are consistent with the hypothesis that lovastatin increases HMG-CoA reductase activity through a feedback mechanism that promoted increased cholesterol synthesis, biliary lipid secretion, and elevated blood cholesterol. There was an apparent coupling of biliary cholesterol output with phospholipids but not with bile salts. Although lovastatin also increased microsomal HMG-CoA reductase activity in humans, cholesterol synthesis is not stimulated but is inhibited. This may be explained by higher permeability of the microsomal membranes for lovastatin. Thus the effect of HMG-CoA reductase inhibitors on cholesterol synthesis in different species should then depend on the properties of microsomal membranes.
Modulation of the stimulatory effect of pregnenolone-16α-carbonitrile on biliary cholesterol output in the rat by manipulation of the rate of hepatic cholesterol synthesis
