Inhibition of cholesterol ester transfer protein CGS 25159 and changes in lipoproteins in hamsters.
As a result of screening, several isoflavans were identified to be antagonists of cholesterol ester transfer protein (CETP) activity. The present study evaluates CGS 25159, a synthetic isoflavan, as a putative inhibitor of CETP activity of human and hamster plasma. Determined by [3]CE transfer from HDL to VLDL + LDL fraction or by fluorescent-CE transfer assay, CGS 25159 inhibited CETP in both human plasma bottom fraction (d = 1.21 g/ml) and in plasma from Golden Syrian Hamsters with an IC50 < 10 microM. The compound also inhibited (IC 50 approximately equal to 15 microM) the reciprocal transfer of triglycerides in the incubated whole plasma from normal and hyperlipidemic hamsters. When orally administered to normolipidemic hamsters, CGS 25159 (10 mg/kg, 4 days) reduced plasma transfer activity by 35-60%. Treatment with CGS 25159 (10 and 30 mg/kg, p.o.) resulted in dose dependent and time dependent changes in CETP activity. After two weeks of treatment at 10 mg/kg, the changes in VLDL + LDL cholesterol, total triglycerides and HDL cholesterol were -22 +/- 4.6*, -23 +/- 7.5 and +10 +/- 2.8%, respectively. The corresponding changes at 30 mg/kg were -28 +/- 5.5*, -38 +/- 6.8* and +29 +/-4.4.*%, (*, P, 0.05; mean +/- S.E.M., n = 6). A single spin gradient density ultracentrifugation of plasma lipoproteins and treated animals showed an increase in HDL cholesterol and a redistribution to larger HDL particles. These data support the contention that pharmacological down regulation of CETP activity could result in favorable changes in lipoprotein profile.
Kothari
H V
HV
Pharmaceuticals Division, CIBA Corporation, Summit NJ 07901, USA.
Poirier
K J
KJ
Lee
W H
WH
Satoh
Y
Y
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D008647:Mesocricetus
D001578:Benzopyrans; C506642:CETP protein, human; C106476:CGS 25159; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D002791:Cholesterol, Dietary; D006023:Glycoproteins; D008055:Lipids