Involvement of cholesterol in the inhibitory effect of dimethyl-β-cyclodextrin on P-glycoprotein and MRP2 function in Caco-2 cells
Involvement of cholesterol in the inhibitory effect of dimethyl-β-cyclodextrin on P-glycoprotein and MRP2 function in Caco-2 cells
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DOI：
10.1016/s0014-5793(03)00059-0
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发表时间：
2003-02-11
期刊：
影响因子：
3.5
通讯作者：
Uekama, K
中科院分区：
文献类型：
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作者：
Yunomae, K;Arima, H;Uekama, K
我们比较了不同环糊精(CyDS)对P-糖蛋白(P-gp)和多药耐药相关蛋白2(MRP2)功能的抑制作用，并考察了胆固醇对2，6-二-O-甲基-β-环糊精(DM-β-CyD)抑制Caco-2细胞单层P-糖蛋白和多药耐药相关蛋白2功能的作用。在不同的Cyds中，DM-β-Cyd显著削弱P-gp和MRP2的外排活性。DM-β-Cyd使Caco-2细胞单层转运缓冲液中的P-gp和MRP2释放，降低Caco-2细胞单层小窝中胆固醇和P-gp和MRP2的含量，但不能降低Caco-2细胞单层小窝中的P-gp和MRP2的含量。另一方面，DM-β-CyD不改变MDR1和MRP2的mRNA水平。因此，这些结果提示，DM-β-Cyd对P-gp和MRP2功能的抑制作用，至少部分可以归因于DM-β-Cyd处理Caco-2细胞单层后，这些转运蛋白作为次要效应从根尖膜释放到基质中，通过清除Caco-2细胞单层中的胆固醇。(C)2003年，埃尔塞维尔科学公司代表欧洲生化学会联合会出版。
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. (C) 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.