Journal of Lipid Research (Aug 1999)
Comparison of the capacity of β-cyclodextrin derivatives and cyclophanes to shuttle cholesterol between cells and serum lipoproteins
Abstract
Previous studies from this laboratory have demonstrated that low concentrations of cyclodextrins (<1.0 mm), when added to serum, act catalytically as cholesterol shuttles to accelerate the exchange of free cholesterol between cells and serum lipoproteins. As cholesterol shuttles, cyclodextrins have the potential to serve as pharmacological agents for modifying cholesterol metabolism. In the present study, we have quantitated the cholesterol-shuttling capacity of a series of newly synthesized β-cyclodextrin derivatives (βCDs), with varying structure, and two double-decker cyclophanes. The general protocol is as follows. [3H]cholesterol-labeled CHOK1 cells are incubated for 2 h with the test compounds alone or together with 5% human serum, and efflux of the cellular [3H]cholesterol is measured. As methyl β-cyclodextrin (MβCD) served as the basis for comparison, initial experiments were conducted that demonstrated there was a dose-dependent stimulation of cell cholesterol efflux as the concentration of MβCD increased, with an EC50 that was calculated to be 0.05 mm. To determine the cholesterol-shuttling capacity of the newly synthesized compounds, cell cholesterol efflux is measured when the compounds are present alone, at a concentration of 0.05 mm, or together with 5% human serum. Our results demonstrate that the double-decker cyclophanes are the most efficient cholesterol shuttles. Under our experimental conditions, methyl β-cyclodextrin (MβCD) approximately doubles the efflux of cell cholesterol to serum, whereas one of the double-decker cyclophanes produces a 4-fold stimulation in efflux. Four of the β-cyclodextrin derivatives (βCDs) display shuttling ability similar to that of MβCD. Furthermore, there does not appear to be a structural pattern among the other βCDs which could explain their shuttling capacity.—Christian, A. E., H-S. Byun, N. Zhong, M. Wanunu, T. Marti, A. Fürer, F. Diederich, R. Bittman, and G. H. Rothblat. Comparison of the capacity of β-cyclodextrin derivatives and cyclophanes to shuttle cholesterol between cells and serum lipoproteins. J. Lipid Res. 1999. 40: 1475–1482.
