PRAVASTATIN INHIBITS CELLULAR CHOLESTEROL-SYNTHESIS AND INCREASES LOW-DENSITY-LIPOPROTEIN RECEPTOR ACTIVITY IN MACROPHAGES - IN-VITRO AND IN-VIVO STUDIES

1 Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) inhib itor, is a highly selective inhibitor of hepatic cholesterol synthesis . We studied the in vivo and in vitro effects of pravastatin on macrop hage cholesterol metabolism. 2 The effects of incubating pravastatin w ith human monocyte derived macrophages (HMDM), mouse peritoneal macrop hages (MPM) and a J-774 A.1 macrophagelike cell line, on macrophage ch olesterol synthesis, cellular degradation of native low density lipopr otein (LDL) and modified LDL, cholesterol efflux from these cells and the cholesterol esterification rate were determined. 3 Pravastatin was administered either as one 40 mg dose or 40 mg daily for 8 weeks to n ormocholesterolaemic and hypercholesterolaemic individuals. The effect s on cholesterol synthesis and degradation in monocytes derived from t hese subjects were studied. 4 In vitro, pravastatin resulted in a dose -dependent inhibition of macrophage cholesterol synthesis, Cellular de gradation of native LDL increased by 119% in the presence of 0.1 mg ml (-1) pravastatin. Degradation of both acetyl LDL and oxidized LDL was unaffected. Small concentrations of pravastatin (up to 0.19 mu g ml(-1 )) increased the cellular cholesterol esterification rate after incuba tion with LDL, but higher concentrations resulted in an inhibition of the esterification. 5 Single dose pravastatin administration caused a reduction in cholesterol synthesis by the subjects own HMDM by 62% and 47% in normocholesterolaemic and hypercholesterolaemic individuals, r espectively. Chronic administration resulted in a 55% inhibition of ch olesterol synthesis and a 57% increase in LDL degradation. 6 The resul ts indicate that the selective uptake of pravastatin shown for hepatoc ytes can be extended to macrophages. Pravastatin can inhibit cholester ol accumulation in cells of the arterial wall and by so doing exhibits an additional anti-atherogenic characteristic.