| Autor: |
Bensch WR; Division of Cardiovascular Research, Eli Lilly and Company, Indianapolis, Indiana, USA. wrbensch@lilly.com, Gadski RA, Bean JS, Beavers LS, Schmidt RJ, Perry DN, Murphy AT, McClure DB, Eacho PI, Breau AP, Archer RA, Kauffman RF |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 1999 Apr; Vol. 289 (1), pp. 85-92. |
| Abstrakt: |
The action of LY295427 [(3alpha,4alpha, 5alpha)-4-(2-propenylcholestan-3-ol)], a compound that derepresses low-density lipoprotein receptor (LDL-R) expression in a cell-based model, was examined in hamsters. It was found that the compound does not have an effect in normal chow-fed hamsters, in which LDL-R levels are not repressed, but exerts a marked hypocholesterolemic effect (>70% decrease) in cholesterol-coconut oil-fed hamsters, in which LDL-R is repressed. In this model, there is a dose-response for cholesterol lowering with an approximate ED50 value of 40 mg/kg/day and an inverse relationship between serum cholesterol and serum LY295427 levels. LDL-R mRNA is increased (2-fold) and liver cholesterol ester content is decreased (>90%). Unlike the 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor lovastatin, the decreased serum cholesterol is confined to the non-high-density lipoprotein fraction. Furthermore, LY295427 does not affect cholesterol biosynthesis, and it does not have a significant effect on cholesterol absorption. These data suggest that LY295427 acts in the hypercholesterolemic hamster by derepressing LDL-R transcription, thereby enhancing cholesterol clearance from the blood. The results with LY295427 suggest that compounds that act to increase LDL-R may represent a novel approach in the pharmacotherapy for hypercholesterolemia. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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