DIFFERENT EFFECTS OF 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE INHIBITORS ON STEROL SYNTHESIS IN VARIOUS HUMAN CELL-TYPES

The three vastatins examined, lovastatin, simvastatin and pravastatin, are equally strong inhibitors of the sterol synthesis in human hepato cytes in culture with IC50-values of 4.1, 8.0 and 2.0 nM, respectively . However, in the human extrahepatic cells: umbilical vascular endothe lial cells, retinal pigment epithelial cells, comea fibroblasts and gr anulosa cells, pravastatin was much less inhibiting the sterol synthes is than lovastatin or simvastatin. It was observed as well that longer incubation with the vastatins resulted in higher IC50-values. In orde r to show that the feedback regulation mechanism for 3-hydroxy-3-methy lglutaryl-coenzyme A reductase was involved in this phenomena mRNA lev els were measured in human vascular endothelial cells after incubation with the vastatins for 3.5 h and for 20 h. Indeed, lovastatin and sim vastatin gave rise to higher levels of HMG-CoA reductase mRNA after 20 h than after 3.5 h of incubation. The differences observed in differe nt human cell types can be explained by supposing that pravastatin is transported into the human hepatocyte via a liver-specific transporter . This was supported by the results of uptake experiments with C-14-la belled pravastatin and C-14-labelled simvastatin into human hepatocyte s compared to that into human umbilical endothelial cells (as an examp le of an extrahepatic cell type). [C-14]-Simvastatin was associated wi th both cell types, whereas [C-14]-pravastatin was hardly associated w ith human endothelial cells, but to a similar extent as [C-14]-simvast atin with human hepatocytes.