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The Journal of Lipid Research, Vol. 40, 1475-1482, August 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Comparison of the capacity of ß-cyclodextrin derivatives and cyclophanes to shuttle cholesterol between cells and serum lipoproteins

Correspondence to: George H. Rothblat

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 ß-cyclodextrin derivatives (ßCDs), 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 ß-cyclodextrin (MßCD) 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 MßCD 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 ß-cyclodextrin (MßCD) 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 ß-cyclodextrin derivatives (ßCDs) display shuttling ability similar to that of MßCD. Furthermore, there does not appear to be a structural pattern among the other ßCDs 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 ß-cyclodextrin derivatives and cyclophanes to shuttle cholesterol between cells and serum lipoproteins. J. Lipid Res. 1999. 40: 1475;–1482.

Supplementary key words: cholesterol, cyclodextrins, efflux, cyclophanes, tissue culture cells

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