Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and ATPase activities by interaction with dietary flavonoids

The 190-kDa phosphoglycoprotein multidrug resistance protein 1 (MRP1) (ABCC 1) confers resistance to a broad spectrum of anticancer drugs and also acti vely transports certain xenobiotics with reduced glutathione (GSH) (cotrans port) as well as conjugated organic anions such as leukotriene C-4 (LTC4). In the present study, we have investigated a series of bioflavonoids for th eir ability to influence different aspects of MRP1 function. Most flavonoid s inhibited MRP1-mediated LTC4 transport in membrane vesicles and inhibitio n by several flavonoids was enhanced by GSH. Five of the flavonoids were co mpetitive inhibitors of LTC4 transport (K-i, 2.4-21 muM) in the following r ank order of potency: kaempferol. apigenin (+ GSH). quercetin. myricetin. n aringenin (+ GSH). These flavonoids were less effective inhibitors of 17 be ta -estradiol 17 beta-(D-glucuronide) transport. Moreover, their rank order of inhibitory potency for this substrate differed from that for LTC4 trans port inhibition but correlated with their relative lipophilicity. Several f lavonoids, especially naringenin and apigenin, markedly stimulated GSH tran sport by MRP1, suggesting they may be cotransported with this tripeptide. Q uercetin inhibited the ATPase activity of purified reconstituted MRP1 but s timulated vanadate-induced trapping of 8-azido-alpha-[P-32]ADP by MRP1. In contrast, kaempferol and naringenin stimulated both MRP1 ATPase activity an d trapping of ADP. In intact MRP1-overexpressing cells, quercetin reduced v incristine resistance from 8.9- to 2.2-fold, whereas kaempferol and naringe nin had no effect. We conclude that dietary flavonoids may modulate the org anic anion and GSH transport, ATPase, and/or drug resistance-conferring pro perties of MRP1. However, the activity profile of the flavonoids tested dif fered from one another, suggesting that at least some of these compounds ma y interact with different sites on the MRP1 molecule.