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.
Nagata
Y
Y
Central Research Laboratories, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.
Hidaka
Y
Y
Ishida
F
F
Kamei
T
T
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D002788:Cholesterol Esters / Q000096:biosynthesis; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008113:Liver Neoplasms / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011973:Receptors, LDL / Q000032:analysis; D019821:Simvastatin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000924:Anticholesteremic Agents; D002788:Cholesterol Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D011374:Progesterone; D002784:Cholesterol; C063287:simvastatin acid; D008148:Lovastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases