Modulation of Multidrug Resistance Protein 1 (MRP1/ABCC1) Transport and ATPase Activities by Interaction with Dietary Flavonoids
- Elaine M. Leslie1,2,
- Qingcheng Mao2,
- Curtis J. Oleschuk1,2,
- Roger G. Deeley2 and
- Susan P. C. Cole1,2
- 1Department of Pharmacology and Toxicology (E.M.L., C.J.O., S.P.C.C.) and the 2Cancer Research Laboratories (E.M.L., Q.M., C.J.O., R.G.D., S.P.C.C.), Queen's University, Kingston, Ontario, Canada
Abstract
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 (K i, 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 17β-estradiol 17β-(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-α-[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.
Footnotes
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Send reprint requests to: Dr. Susan P. C. Cole, Cancer Research Laboratories, Room 328, Botterell Hall, Queen's University, Kingston, Ontario, Canada, K7L 3N6. E-mail:coles{at}post.queensu.ca
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This work was supported by a grant (MT-10519) from the Medical Research Council of Canada. E.M.L. and C.J.O. are recipients of Medical Research Council of Canada Doctoral Awards, and E. M. L. is the past recipient of an Ontario Graduate Scholarship. R.G.D. is the Stauffer Cancer Research Professor of Queen's University and S.P.C.C. is a Senior Scientist of Cancer Care Ontario.
- Abbreviations:
- MRP1
- human multidrug resistance protein 1
- ABC
- ATP-binding cassette
- NBD
- nucleotide binding domain
- LTC4
- leukotriene C4
- E217βG
- 17β-estradiol 17-(β-d-glucuronide)
- GSH
- reduced glutathione
- CFTR
- cystic fibrosis transmembrane conductance regulator
- DTT
- dithiothreitol
- GSSG
- glutathione disulfide (oxidized glutathione)
- HPLC
- high-performance liquid chromatography
- DMSO
- dimethyl sulfoxide
- VRP
- verapamil
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- Received October 12, 2000.
- Accepted January 12, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
