1 Glibenclamide, a sulphonylurea widely used for the treatment of non-insulin-dependent diabetes mellitus, has been shown to inhibit the activities of various ATP-binding cassette (ABC) transporters. In the present study, its e ects towards multidrug resistance protein 1 (MRP1), an ABC e ux pump conferring multidrug resistance and handling organic anions, were investigated. 2 Intracellular accumulation of calcein, an anionic dye substrate for MRP1, was strongly increased by glibenclamide in a dose-dependent manner in MRP1-overexpressing lung tumour GLC4/Sb30 cells through inhibition of MRP1-related calcein e ux. By contrast, glibenclamide did not alter calcein levels in parental control GLC4 cells. Another sulphonylurea, tolbutamide, was however without e ect on calcein accumulation in both GLC4/Sb30 and GLC4 cells. 3 Glibenclamide used at 12.5 mM was, moreover, found to strongly enhance the sensitivity of GLC4/Sb30 cells towards vincristine, an anticancer drug handled by MRP1. 4 E ux of carboxy-2',7'-dichloro¯uorescein, an anionic dye handled by the ABC transporter MRP2 sharing numerous substrates with MRP1 and expressed at high levels in liver, was also strongly inhibited by glibenclamide in isolated rat hepatocytes. 5 In summary, glibenclamide reversed MRP1-mediated drug resistance likely through inhibiting MRP1 activity and blocked organic anion e ux from MRP2-expressing hepatocytes. Such e ects associated with the known inhibitory properties of glibenclamide towards various others ABC proteins suggest that this sulphonylurea is a general inhibitor of ABC transporters.
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