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Vol. 31, Issue 1, 11-15, January 2003
Department of Pharmacology 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 apparent
Km and Vmax for
GSH uptake in the presence of 30 µM apigenin were 116 µM and 666 pmol mg
& Toxicology (E.M.L., S.P.C.C.)
and the Cancer Research Laboratories
(E.M.L., R.G.D.,
S.P.C.C.)
Queen's University, Kingston,
Ontario,
Canada
1 min1, 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.
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