Comparison of the effect of six compactin-related compounds on cholesterol synthesis in five human cell types.

We have investigated the effect of six compactin-related compounds--mevinolin, compactin, ML-236A, monacolin X, monacolin L and dihydromonacolin L--on cholesterol synthesis in human umbilical vein endothelial cells, human small intestine epithelial cells, human hepatoma cell line HEP G2, normal human skin fibroblasts and in skin fibroblasts from a patient with familial homozygous hypercholesterolemia. The inhibition of cholesterol synthesis was found to depend on both the cell type and the type of compound used. The most effective compounds were mevinolin and compactin. Monacolin X, monacolin L and ML-236A were less effective, and dihydromonacolin L was the least efficacious. Endothelial and epithelial cells were sensitive to very low concentrations of inhibitors (IC50 = 1.0-30 pg/mL), HEP G2 cells required higher concentrations (IC50 = 0.01-66 ng/mL) and fibroblasts needed even higher concentrations (IC50 = 0.1-200 ng/mL). Lactone and acid forms of the inhibitors were equally active. None of the inhibitors had any effect on either protein or fatty acid synthesis in any of the cell types studied. It can be concluded that different compactin-related compounds show a range of potencies as cholesterol synthesis inhibitors and a dose-dependent tissue-selectivity.