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Vol. 59, Issue 5, 1171-1180, May 2001
Department of Pharmacology and Toxicology (E.M.L., C.J.O.,
S.P.C.C.) and the Cancer Research Laboratories (E.M.L., Q.M., C.J.O.,
R.G.D., S.P.C.C.), Queen's University, Kingston, Ontario, Canada
The 190-kDa phosphoglycoprotein multidrug resistance protein 1 (MRP1)
(ABCC1) confers resistance to a broad spectrum of anticancer drugs and
also actively transports certain xenobiotics with reduced glutathione
(GSH) (cotransport) as well as conjugated organic anions such as
leukotriene C4 (LTC4). In the present study, we have investigated a series of bioflavonoids for their ability to
influence different aspects of MRP1 function. Most flavonoids inhibited
MRP1-mediated LTC4 transport in membrane vesicles and inhibition by several flavonoids was enhanced by GSH. Five of the
flavonoids were competitive inhibitors of LTC4 transport
(Ki, 2.4-21 µM) in the following rank
order of potency: kaempferol > apigenin (+ GSH) > quercetin > myricetin > naringenin (+ GSH). These
flavonoids were less effective inhibitors of 17
-estradiol 17-(D-glucuronide) transport. Moreover, their rank order
of inhibitory potency for this substrate differed from that for
LTC4 transport inhibition but correlated with their
relative lipophilicity. Several flavonoids, especially naringenin and
apigenin, markedly stimulated GSH transport by MRP1, suggesting they
may be cotransported with this tripeptide. Quercetin inhibited the
ATPase activity of purified reconstituted MRP1 but stimulated
vanadate-induced trapping of 8-azido-
-[32P]ADP by
MRP1. In contrast, kaempferol and naringenin stimulated both MRP1
ATPase activity and trapping of ADP. In intact MRP1-overexpressing cells, quercetin reduced vincristine resistance from 8.9- to 2.2-fold, whereas kaempferol and naringenin had no effect. We conclude that dietary flavonoids may modulate the organic anion and GSH transport, ATPase, and/or drug resistance-conferring properties of MRP1. However,
the activity profile of the flavonoids tested differed from one
another, suggesting that at least some of these compounds may interact
with different sites on the MRP1 molecule.
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