Print Email Facebook Twitter Structural requirements for the flavonoid-mediated modulation of glutathione S-transferase P1-1 and GS-X pump activity in MCF7 breast cancer cells Title Structural requirements for the flavonoid-mediated modulation of glutathione S-transferase P1-1 and GS-X pump activity in MCF7 breast cancer cells Author van Zanden, J.J. Geraets, L. Wortelboer, H.M. van Bladeren, P.J. Rietjens, I.M.C.M. Cnubben, N.H.P. TNO Voeding Publication year 2004 Abstract The objective of this study was to investigate the structural requirements necessary for inhibition of glutathione S-transferase P1-1 (GSTP1-1) and GS-X pump (MRP1 and MRP2) activity by structurally related flavonoids, in GSTP1-1 transfected MCF7 cells (pMTG5). The results reveal that GSTP1-1 activity in MCF7 pMTG5 cells can be inhibited by some flavonoids. Especially galangin was able to inhibit almost all cellular GSTP1-1 activity upon exposure of the cells to a concentration of 25μM. Other flavonoids like kaempferol, eriodictyol and quercetin showed a moderate GSTP1-1 inhibitory potential. For GSTP1-1 inhibition, no specific structural requirements necessary for potent inhibition could be defined. Most flavonoids appeared to be potent GS-X transport inhibitors with IC50 values ranging between 0.8 and 8μM. Luteolin and quercetin were the strongest inhibitors with IC50 values of 0.8 and 1.3μM, respectively. Flavonoids without a C2-C3 double bond like eriodictyol, taxifolin and catechin did not inhibit GS-X pump activity. The results of this study demonstrate that the structural features necessary for high potency GS-X pump inhibition by flavonoids are (1) the presence of hydroxyl groups, especially two of them generating the 3′,4′- catechol moiety; and (2) a planar molecule due to the presence of a C2-C3 double bond. Other factors, like lipophilicity and the total number of hydroxyl groups do not seem to be dominating the flavonoid-mediated GS-X pump inhibition. To identify the GS-X pump responsible for the DNP-SG efflux in MCF7 cells, the effects of three characteristic flavonoids quercetin, flavone and taxifolin on MRP1 and MRP2 activity were studied using transfected MDCKII cells. All three flavonoids as well as the typical MRP inhibitor (MK571) affected MRP1-mediated transport activity in a similar way as observed in the MCF7 cells. In addition, the most potent GS-X pump inhibitor in the MCF7 cells, quercetin, did not affect MRP2-mediated transport activity. These observations clearly indicate that the GS-X pump activity in the MCF7 cells is likely to be the result of flavonoid-mediated inhibition of MRP1 and not MRP2. Altogether, the present study reveals that a major site for flavonoid interaction with GSH-dependent toxicokinetics is the GS-X pump MRP1 rather than the conjugating GSTP1-1 activity itself. Of the flavonoids shown to be most active especially quercetin is frequently marketed in functional food supplements. Given the physiological levels expected to be reached upon supplement intake, the IC50 values of the present study point at possible flavonoid-drug and/or flavonoid-xenobiotic interactions especially regarding transport processes involved in toxicokinetics. © 2004 Elsevier Inc. All rights reserved. Subject Biology ToxicologyPhysiological Sciences1-chloro-2,4-dinitrobenzene50% inhibition concentrationCDNBDNP-SGGlutathioneGlutathione conjugateGlutathione S-transferaseGS-XGSHGSTIC50MRPMultidrug resistance associated proteinP-gpS-(2,4-dinitrophenyl)glutathione3',4' dihydroxyflavonecarboncatechincatechol derivativeeriodictyolflavanoidflavone derivativegalaninglutathione transferasehydroxyl groupkaempferolluteolinmorinmultidrug resistance protein 1multidrug resistance protein 2myricetinquercetintaxifolinunclassified druganimal cellarticlebreast cancercell strain MCF 7chemical bondcontrolled studydrug activitydrug potencyenzyme activityenzyme inhibitiongenetic transfectionhumanhuman cellIC 50lipophilicitynonhumanpriority journalstructure activity relationtoxicokineticsBiological TransportBreast NeoplasmsCarrier ProteinsDrug Resistance, MultipleDrug Resistance, NeoplasmFlavonoidsGlutathioneGlutathione S-Transferase piGlutathione TransferaseHumansIsoenzymesMembrane Transport ModulatorsMembrane Transport ProteinsMultidrug Resistance-Associated ProteinsStructure-Activity RelationshipTumor Cells, Cultured To reference this document use: http://resolver.tudelft.nl/uuid:b7683498-ca59-428c-be14-5dabdb7bb4b4 DOI https://doi.org/10.1016/j.bcp.2003.12.032 TNO identifier 237714 ISSN 0006-2952 Source Biochemical Pharmacology, 67 (8), 1607-1617 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.