Effect of simvastatin (MK-733) on the regulation of cholesterol synthesis in Hep G2 cells.

A new antihypercholesterolemic drug, simvastatin (MK-733), which is a prodrug of a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, inhibited cholesterol synthesis from [14C]acetate concentration dependently without inhibiting it from [3H]mevalonate in Hep G2 cells. Therefore, MK-733 is thought to be converted to L-654,969, the active beta-hydroxy acid form of MK-733 in the cells and/or medium. MK-733 inhibited cholesterol ester synthesis, but did not affect phospholipid, free fatty acid and triacylglycerol synthesis. This compound increased HMG-CoA reductase activity concentration dependently and raised the specific binding, internalization and degradation of 125I-labeled low density lipoprotein by Hep G2 cells. Another HMG-CoA reductase inhibitor, pravastatin (CS-514), also behaved like MK-733. However, its potency was far less than that of MK-733.