No abstract

No abstract

. The objective of this study was to compare in cultured human hepatocytes or Hep G2 cells, changes in the fate of unesterified low density lipoprotein (LDL)‐cholesterol induced by crilvastatin, a new cholesterol lowering drug and a reference statin, simvastatin. . The experiments were carried out for 20 h, each well contained 4.2 × 105/cm2 Hep G2 cells or 0.5 × 105/cm2 human hepatocytes, 130 μm ursodeoxycholate, 0.68 μCi or 1.59 μCi unesterified human [14C]‐LDL‐cholesterol, crilvastatin or simvastatin at 0 or 50 μm (both cell types) or 300 μm (Hep‐G2 cells). Incubation with the two drugs resulted in increased amounts of unesterified [14C]‐LDL‐cholesterol taken by the two cell types, compared to control. . Crilvastatin 50 μm led to significantly higher quantities of [14C]‐glyco‐ and [14C]‐tauro‐conjugated bile salts, compared to simvastatin. Statins reduced the apo B100 level secreted by the two cell types (simvastatin) or human hepatocytes (crilvastatin). Crilvastatin enhanced both the level of apo A1 secreted by the Hep G2 cells and the level of APF, a high density lipoprotein (HDL) and biliary apoprotein. . Crilvastatin not only acts by stimulating LDL‐cholesterol uptake by hepatocytes, but also by enhancing the catabolism of LDL‐cholesterol in bile salts and probably by stimulating HDL and/or bile component secretion. Such a mechanism was not previously described for HMG CoA reductase inhibitors. Our results on APF show that this apoprotein could be considered also as an indicator of changes in bile and/or HDL compartments. . The human hepatocyte model appeared to be a suitable and relevant model in the pharmacological***metabolic experiments carried out in this study. It led to more consistent data than those obtained with Hep G2 cells.

The aim of these experiments was to determine the effect of crilvastatin, a new cholesterol lowering agent, on the metabolism of unesterified low density lipoprotein (LDL)‐cholesterol by rat freshly isolated hepatocytes. This preclinical model was developed as an alternative to in vivo experiments, to mimic the metabolic effects of a molecule on its target cells and to define optimal conditions for future experimentation on human hepatocytes. Cells were obtained from normolipidaemic or hypercholesterolaemic rats, hypercholesterolaemia was nutritionally induced. Incubations were performed in a medium containing 600 μm taurocholate and 50 μm or 300 μm crilvastatin. This molecule was shown in vitro to be carried by physiological transporters, i.e., albumin‐bile salt micellar associations and LDL. Crilvastatin induced a significance increase in the synthesis and secretion by hepatocytes of bile salts resulting from the metabolism of unesterified LDL‐cholesterol in both normolipidaemic and hypercholesterolaemic rats. Stimulation involved non‐conjugated as well as tauro‐ and glyco‐conjugated bile salts. These findings corroborate preliminary studies showing in vivo that crilvastatin enhances the secretion of bile acids by stimulating the uptake and incorporation of LDL‐cholesterol by the liver.