Inhibition of cholesterol ester transfer protein by 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 [3H]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 μM. The compound also inhibited (IC50≈15 μM) 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 from 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.