Bioflavonoid Stimulation of Glutathione Transport by the 190-kDa Multidrug Resistance Protein 1 (MRP1)

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Abstract
In tumor cells, the human multidrug resistance protein 1 (MRP1), confers resistance to a broad spectrum of anticancer agents. MRP1 is also expressed in many normal tissues where it acts as an ATP-dependent transporter of organic anions. Reduced glutathione (GSH) is transported by MRP1 with very low affinity, and certain MRP1 substrates are transported in association with this tripeptide. Previous studies have shown that various dietary flavonoids stimulate the ATPase activity of MRP1 and inhibit transport of its conjugated organic anion substrates but are poor reversers of MRP1-mediated drug resistance. In contrast, many of the same flavonoids markedly stimulate GSH transport by MRP1. In the present study, we found that stimulation of GSH transport in inside-out MRP1-enriched membrane vesicles by apigenin, naringenin, genistein, and quercetin was maximum at a concentration of 30 μM. Apigenin was the most efficacious of the four bioflavonoids, showing a maximal 6-fold increase over basal levels of GSH transport. The apparentKm and Vmax for GSH uptake in the presence of 30 μM apigenin were 116 μM and 666 pmol mg−1 min−1, respectively. Chemosensitivity assays with control-transfected and MRP1-transfected HeLa cell lines showed that the IC50 values for apigenin, naringenin, genistein, and quercetin were similar, demonstrating that overexpression of MRP1 does not confer resistance to these bioflavonoids. Our results suggest that flavonoids stimulate MRP1-mediated GSH transport by increasing the apparent affinity of the transporter for GSH but provide no evidence that a cotransport mechanism is involved.