title: Involvement of cholesterol in the inhibitory effect of dimethyl-beta-cyclodextrin on P-glycoprotein and MRP2 function in Caco-2 cells.
abstract: We compared the inhibitory effect of various cyclodextrins (CyDs) on P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) function and examined the contribution of cholesterol to the inhibitory effect of 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) on the efflux activity of the function in Caco-2 cell monolayers. Of various CyDs, DM-beta-CyD significantly impaired the efflux activity of P-gp and MRP2. DM-beta-CyD released P-gp and MRP2 from the monolayers in the apical side's transport buffer and decreased the extent of cholesterol as well as P-gp and MRP2 in caveolae of Caco-2 cell monolayers, but not caveolin and flotillin-1. On the other hand, DM-beta-CyD did not change MDR1 and MRP2 mRNA levels. Therefore, these results suggest that the inhibitory effect of DM-beta-CyD on P-gp and MRP2 function, at least in part, could be attributed to the release of these transporters from the apical membranes into the medium as secondary effects through cholesterol-depletion in caveolae after treatment of Caco-2 cell monolayers with DM-beta-CyD.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Yunomae
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Kaneto
authors.initials: K
authors.lastname: Uekama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D021941:Caveolae / Q000737:chemistry; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism*; D003505:Cyclodextrins / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047392:beta-Cyclodextrins
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002784:Cholesterol; D003505:Cyclodextrins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D047392:beta-Cyclodextrins; C000715087:ABCC2 protein, human; C108732:methyl-beta-cyclodextrin; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin; C421109:multidrug resistance-associated protein 1