title: The effect of quercetin phase II metabolism on its MRP1 and MRP2 inhibiting potential.
abstract: The present study characterises the effect of phase II metabolism, especially methylation and glucuronidation, of the model flavonoid quercetin on its capacity to inhibit human MRP1 and MRP2 activity in Sf9 inside-out vesicles. The results obtained reveal that 3'-O-methylation does not affect the MRP inhibitory potential of quercetin. However, 4'-O-methylation appeared to reduce the potential to inhibit both MRP1 and MRP2. In contrast, glucuronidation in general, and especially glucuronidation at the 7-hydroxylmoiety, resulting in 7-O-glucuronosyl quercetin, significantly increased the potential of quercetin to inhibit MRP1 and MRP2 mediated calcein transport with inhibition of MRP1 being generally more effective than that of MRP2. Overall, the results of this study reveal that the major phase II metabolites of quercetin are equally potent or even better inhibitors of human MRP1 and MRP2 than quercetin itself. This finding indicates that phase II metabolism of quercetin could enhance the potential use of quercetin- or flavonoids in general-as an inhibitor to overcome MRP-mediated multidrug resistance.
authors.affiliation: Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA, Wageningen, The Netherlands. jvanzanden@gmail.com
authors.forename: Jelmer J
authors.initials: JJ
authors.lastname: van Zanden
authors.forename: Hester
authors.initials: H
authors.lastname: van der Woude
authors.forename: Judith
authors.initials: J
authors.lastname: Vaessen
authors.forename: Mustafa
authors.initials: M
authors.lastname: Usta
authors.forename: Heleen M
authors.initials: HM
authors.lastname: Wortelboer
authors.forename: Nicole H P
authors.initials: NH
authors.lastname: Cnubben
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D011794:Quercetin / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats
chemical_list: D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011794:Quercetin; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1