Research ArticlesInteractions of azole antifungal agents with the human breast cancer resistance protein (BCRP)
Section snippets
INTRODUCTION
The human breast cancer resistance protein (BCRP, gene symbol ABCG2) belongs to the subfamily G of the large ATP‐binding cassette (ABC) transporter superfamily.1., 2., 3. Recent studies have illustrated that BCRP is capable of transporting a broad range of substrates, from highly lipophilic anticancer agents (e.g., mitoxantrone and the anthracyclines) to hydrophilic organic anions (e.g., estrone‐3‐sulfate and 17β‐estradiol 17‐(β‐D‐glucuronide)).4., 5., 6. The molecular mechanism by which BCRP
Materials
Ketoconazole and fluconazole were purchased from Sigma (St. Louis, MO). Itraconazole was from Research Diagnostics (Flanders, NJ). Voriconazole was a gift from Dr. Kenneth E. Thummel (Department of Pharmaceutics, University of Washington, Seattle, WA). [3H]ketoconazole (10 Ci/mmol) was from American Radiolabeled Chemicals (St. Louis, MO). Pheophorbide A (PhA) was from Frontier Scientific (Logan, UT). Topotecan was a gift from GlaxoSmithKline (Research Triangle Park, NC). Fumitremorgin C (FTC)
Inhibition of BCRP‐Mediated PhA Efflux by Azole Antifungals
Since PhA is a fluorescent compound and is known to be a specific substrate for BCRP, but not for P‐gp and MRP1,27 it was used as a model BCRP substrate in determining the effects of azole antifungals on BCRP efflux activity. We used BCRP‐overexpressing HEK cells for PhA efflux experiments. We have shown that the HEK cells express little endogenous P‐gp, MRP1, or MRP2.22 In the present study, we further determined the endogenous expression of MRP4 in HEK cells by immunoblotting. No MRP4 was
DISCUSSION
In the present study, we have for the first time investigated the interactions of BCRP with four azole antifungals with different chemical structures (Fig. 1). We found that ketoconazole can inhibit BCRP‐mediated PhA efflux with an IC50 value of approximately 15 µM (Fig. 3). This inhibitory potency is lower than that of FTC which has an IC50 value of approximately 1 µM for BCRP.23 Itraconazole also significantly inhibited BCRP at concentrations below 1 µM (Fig. 2). However, we could not measure
Acknowledgements
We gratefully acknowledge financial support from NIH grant HD044404 (to QM and JDU). The authors thank Dr. Robert W. Robey and Dr. Susan E. Bates (National Cancer Institute, Bethesda, MD) for providing the HEK cell lines. We also acknowledge GlaxoSmithKline (Research Triangle Park, NC) and Dr. Kenneth E. Thummel (Department of Pharmaceutics, University of Washington, Seattle, WA) for providing topotecan and voriconazole, respectively.
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