title: Comparison of the capacity of beta-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 beta-cyclodextrin derivatives (betaCDs), with varying structure, and two double-decker cyclophanes. The general protocol is as follows. [(3)H]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 [(3)H]cholesterol is measured. As methyl beta-cyclodextrin (MbetaCD) 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 MbetaCD increased, with an EC(50) 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 beta-cyclodextrin (MbetaCD) 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 beta-cyclodextrin derivatives (betaCDs) display shuttling ability similar to that of MbetaCD. Furthermore, there does not appear to be a structural pattern among the other betaCDs which could explain their shuttling capacity.
authors.affiliation: Department of Biochemistry, MCP Hahnemann University School of Medicine, Philadelphia, PA 19129, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Christian
authors.forename: H S
authors.initials: HS
authors.lastname: Byun
authors.forename: N
authors.initials: N
authors.lastname: Zhong
authors.forename: M
authors.initials: M
authors.lastname: Wanunu
authors.forename: T
authors.initials: T
authors.lastname: Marti
authors.forename: A
authors.initials: A
authors.lastname: Fürer
authors.forename: F
authors.initials: F
authors.lastname: Diederich
authors.forename: R
authors.initials: R
authors.lastname: Bittman
authors.forename: G H
authors.initials: GH
authors.lastname: Rothblat
mesh_terms: D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003505:Cyclodextrins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000378:metabolism; D004988:Ethers, Cyclic / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D010880:Piperidines / Q000378:metabolism*; D012995:Solubility; D047392:beta-Cyclodextrins; D000097566:Cyclophanes
chemical_list: D002784:Cholesterol; D003505:Cyclodextrins; D004337:Drug Carriers; D004988:Ethers, Cyclic; D008074:Lipoproteins; D010880:Piperidines; D047392:beta-Cyclodextrins; C121239:cyclophane 1; D000097566:Cyclophanes; C121240:cyclophane 2; C031215:betadex