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The effect of quercetin phase II metabolism on its MRP1 and MRP2 inhibiting potential

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Author: Zanden, J.J. van · Woude, H. van der · Vaessen, J. · Usta, M. · Wortelboer, H.M. · Cnubben, N.H.P. · Rietjens, I.M.C.M.
Institution: TNO Kwaliteit van Leven
Source:Biochemical Pharmacology, 2, 74, 345-351
Identifier: 240089
doi: doi:10.1016/j.bcp.2007.04.002
Keywords: Biomedical Research · ABC transporters · Flavonoids · MRP1 · MRP2 · Phase II metabolism · Quercetin · ABC transporter · flavonoid · multidrug resistance protein 1 · multidrug resistance protein 2 · quercetin · animal cell · article · cancer cell culture · cancer chemotherapy · chemical structure · controlled study · enzyme activity · enzyme inhibition · glucuronidation · human · human cell · multidrug resistance · nonhuman · priority journal · rat · Animals · Cell Line, Tumor · Humans · Membrane Transport Proteins · Multidrug Resistance-Associated Proteins · Quercetin · Rats


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. © 2007 Elsevier Inc. All rights reserved.