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Involvement of cholesterol in the inhibitory effect of dimethyl‐β‐cyclodextrin on P‐glycoprotein and MRP2 function in Caco‐2 cells
Author(s) -
Yunomae Kiyokazu,
Arima Hidetoshi,
Hirayama Fumitoshi,
Uekama Kaneto
Publication year - 2003
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)00059-0
Subject(s) - caco 2 , p glycoprotein , multidrug resistance associated protein 2 , cyclodextrin , chemistry , glycoprotein , cholesterol , function (biology) , inhibitory postsynaptic potential , biochemistry , microbiology and biotechnology , atp binding cassette transporter , endocrinology , transporter , biology , in vitro , gene , multiple drug resistance , antibiotics
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‐β‐cyclodextrin (DM‐β‐CyD) on the efflux activity of the function in Caco‐2 cell monolayers. Of various CyDs, DM‐β‐CyD significantly impaired the efflux activity of P‐gp and MRP2. DM‐β‐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‐β‐CyD did not change MDR1 and MRP2 mRNA levels. Therefore, these results suggest that the inhibitory effect of DM‐β‐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‐β‐CyD.