Interplay between MRP Inhibition and Metabolism of MRP Inhibitors: The Case of Curcumin

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• 作者：Heleen M. Wortelboer ; Mustafa Usta ; Astrid E. van der Velde ; Marelle G. Boersma ; Bert Spenkelink ; Jelmer J. van Zanden ; Ivonne M. C. M. Rietjens ; Peter J. van Bladeren ; and Nicole H. P. Cnubben
• 刊名：Chemical Research in Toxicology
• 出版年：2003
• 出版时间：December 2003
• 年：2003
• 卷：16
• 期：12
• 页码：1642 - 1651
• 全文大小：159K
• 年卷期：v.16,no.12(December 2003)
• ISSN：1520-5010

文摘

The multidrug resistance proteins MRP1 and MRP2 are efflux transporters with broadsubstrate specificity, including glutathione, glucuronide, and sulfate conjugates. In the presentstudy, the interaction of the dietary polyphenol curcumin with MRP1 and MRP2 and theinterplay between curcumin-dependent MRP inhibition and its glutathione-dependent metabolism were investigated using two transport model systems. In isolated membrane vesiclesof MRP1- and MRP2-expressing Sf9 cells, curcumin clearly inhibited both MRP1- and MRP2-mediated transport with IC₅₀ values of 15 and 5 ges/entities/mgr.gif">M, respectively. In intact monolayers ofMRP1 overexpressing Madin-Darby canine kidney (MDCKII-MRP1) cells, curcumin alsoinhibited MRP1-mediated activity, although with a 3-fold higher IC₅₀ value than the oneobserved in the vesicle model. Interestingly, MRP2-mediated activity was hardly inhibited inintact monolayers of MRP2-overexpressing MDCKII (MDCKII-MRP2) cells upon exposure tocurcumin, whereas the IC₅₀ value in the vesicle incubations was 5 ges/entities/mgr.gif">M. The difference in extentof inhibition of the MRPs by curcumin in isolated vesicles as compared to intact cells, observedespecially for MRP2, was shown to be due to a swift metabolism of curcumin to two glutathioneconjugates in the MDCKII cells. Formation of both glutathione conjugates was about six timeshigher in the MDCKII-MRP2 cells as compared with the MDCKII-MRP1 cells, a phenomenonthat could be ascribed to the significantly lower glutathione levels in the cell line. The effluxof both conjugates, identified in the present study as monoglutathionyl curcumin conjugates,was demonstrated to be mediated by both MRP1 and MRP2. From dose-response curves withSf9 membrane vesicles, glutathionylcurcumin conjugates appeared to be less potent inhibitorsof MRP1 and MRP2 than their parent compound curcumin. In conclusion, curcumin clearlyinhibits both MRP1- and MRP2-mediated transport, but the glutathione-dependent metabolismof curcumin plays a crucial role in the ultimate level of inhibition of MRP-mediated transportthat can be achieved in a cellular system. This complex interplay between MRP inhibitionand metabolism of MRP inhibitors, the latter affecting the ultimate potential of a compoundfor cellular MRP inhibition, may exist not only for a compound like curcumin but also formany other MRP inhibitors presently or previously developed on the basis of vesicle studies.