title: Differences in hypolipidaemic effects of two statins on Hep G2 cells or human hepatocytes in primary culture.
abstract: 1. 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. 2. The experiments were carried out for 20 h, each well contained 4.2 x 10(5)/cm2 Hep G2 cells or 0.5 x 10(5)/Cm2 human hepatocytes, 130 microM ursodeoxycholate, 0.68 microCi or 1.59 microCi unesterified human [14C]-LDL-cholesterol, crilvastatin or simvastatin at 0 or 50 microM (both cell types) or 300 microM (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. 3. Crilvastatin 50 microM led to significantly higher quantities of [14C]-glyco-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. 4. 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. 5. 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.
authors.affiliation: INSERM, Unité 130, Marseille, France.
authors.forename: T
authors.initials: T
authors.lastname: Clerc
authors.forename: V
authors.initials: V
authors.lastname: Sbarra
authors.forename: N
authors.initials: N
authors.lastname: Domingo
authors.forename: J P
authors.initials: JP
authors.lastname: Rault
authors.forename: N
authors.initials: N
authors.lastname: Diaconescu
authors.forename: V
authors.initials: V
authors.lastname: Moutardier
authors.forename: N
authors.initials: N
authors.lastname: Hasselot
authors.forename: H
authors.initials: H
authors.lastname: Lafont
authors.forename: G
authors.initials: G
authors.lastname: Jadot
authors.forename: C
authors.initials: C
authors.lastname: Laruelle
authors.forename: F
authors.initials: F
authors.lastname: Chanussot
mesh_terms: D000328:Adult; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001053:Apolipoproteins / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D019821:Simvastatin; D014407:Tumor Cells, Cultured
chemical_list: D000924:Anticholesteremic Agents; D001053:Apolipoproteins; D001647:Bile Acids and Salts; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; C081831:crilvastatin; D002784:Cholesterol; D011392:Proline; D008148:Lovastatin; D019821:Simvastatin