AJP - Gastrointestinal and Liver Physiology, Vol 260, Issue 4 625-G630, Copyright © 1991 by American Physiological Society
Increase in serum and bile cholesterol and HMG-CoA reductase by lovastatin in rats
S. Yamauchi, W. G. Linscheer and D. H. Beach
Department of Medicine, State University of New York Health Science Center.
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.
