EFFECT OF PRAVASTATIN, A 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITOR, ON HEPATIC CHOLESTEROL 7-ALPHA-HYDROXYLASE, ACYL-COENZYME-A-CHOLESTEROL ACYLTRANSFERASE, AND BILE LIPID SECRETION IN THE HAMSTER WITH INTACT ENTEROHEPATIC CIRCULATION

The effects of administration of pravastatin, a 3-hydroxy-3-methylglut aryl coenzyme A (HMG-CoA) reductase inhibitor, on hepatic cholesterol 7 alpha-hyroxylase and acyl-coenzyme A: cholesterol acyltransferase (A CAT) activities and bile lipid secretion were investigated in Syrian g olden hamsters. Continuous administration of pravastatin induced no si gnificant changes in hepatic cholesterol content, ACAT and cholesterol 7 alpha-hydroxylase activities, or bile lipid and acid composition, A brupt withdrawal of pravastatin induced increases in hepatic cholester ol content and ACAT activity and no change in hepatic cholesterol 7 al pha-hydroxylase activity, and increased cholesterol saturation in bile . Hepatic cholesterol 7 alpha-hydroxylase activity paralleled hepatic mRNA levels of this enzyme. These results suggest that a change in hep atic cholesterol metabolism induced by continuous administration of pr avastatin maintains a constant net balance of hepatic cholesterol cont ent. In addition, the drug has no deleterious influence on metabolism of bile lipids and acids and related enzymes, except for a transient i ncrease in cholesterol saturation in bile induced by an inappropriate increase in hepatic cholesterol content and a lack of response of chol esterol 7 alpha-hydroxylase activity to changes in hepatic cholesterol content upon abrupt withdrawal of pravastatin.