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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine

Petr Pavek, Gracia Merino, Els Wagenaar, Ellen Bolscher, Martina Novotna, Johan W. Jonker and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics January 2005, 312 (1) 144-152; DOI: https://doi.org/10.1124/jpet.104.073916
Petr Pavek
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Gracia Merino
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Els Wagenaar
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Ellen Bolscher
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Martina Novotna
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Johan W. Jonker
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Alfred H. Schinkel
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Abstract

The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette drug efflux transporter that extrudes xenotoxins from cells, mediating drug resistance and affecting the pharmacological behavior of many compounds. To study the interaction of human wild-type BCRP with steroid drugs, hormones, and the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), we expressed human BCRP in the murine MEF3.8 fibroblast cell line, which lacks Mdr1a/1b P-glycoprotein and Mrp1, and in the polarized epithelial MDCKII cell line. We show that PhIP was efficiently transported by human BCRP in MDCKII-BCRP cells, as was found previously for murine Bcrp1. Furthermore, we show that six out of nine glucocorticoid drugs, corticosterone, and digoxin increased the accumulation of mitoxantrone in the MEF3.8-BCRP cell line, indicating inhibition of BCRP. In contrast, aldosterone and ursodeoxycholic acid had no significant effect on BCRP. The four most efficiently reversing glucocorticoid drugs (beclomethasone, 6α-methylprednisolone, dexamethasone, and triamcinolone) and 17β-estradiol showed a significantly reduced BCRP-mediated transepithelial transport of PhIP by MDCKII-BCRP cells, with the highest reduction of PhIP transport ratio for beclomethasone (from 25.0 ± 1.1 to 2.7 ± 0.0). None of the tested endogenous steroids or synthetic glucocorticoids or digoxin, however, were transported substrates of BCRP. We also identified the H2-receptor antagonist drug cimetidine as a novel efficiently transported substrate for human BCRP and mouse Bcrp1. The generated BCRP-expressing cell lines thus provide valuable tools to study pharmacological and toxicological interactions mediated by BCRP and to identify new BCRP substrates.

Footnotes

  • The Fédération Internationale Pharmaceutique Foundation for Education and Research (The Hague, The Netherlands) funded the Education and Research fellowship of P.P. at The Netherlands Cancer Institute. This work was further supported in part by Grants NKI 2000-2271 and 2000-2143 from the Dutch Cancer Society (to A.H.S. and J.H.M.S., respectively) and Grant 0331/01/D089 from the Grant Agency of the Czech Republic (to P.P.).

  • doi:10.1124/jpet.104.073916.

  • ABBREVIATIONS: BCRP, breast cancer resistance protein; ABC, ATP-binding cassette; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; SN-38, 7-ethyl-10-hydroxycamptothecin; GF120918, elacridar; PSC833, valspodar; PBS, phosphate-buffered saline; MRP, multidrug resistance protein; P-gp, P-glycoprotein; MF, median of fluorescence; MDR, multidrug resistance; Ko143, 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydro-pyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester.

    • Received July 8, 2004.
    • Accepted September 8, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 312 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 312, Issue 1
1 Jan 2005
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine

Petr Pavek, Gracia Merino, Els Wagenaar, Ellen Bolscher, Martina Novotna, Johan W. Jonker and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics January 1, 2005, 312 (1) 144-152; DOI: https://doi.org/10.1124/jpet.104.073916

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine

Petr Pavek, Gracia Merino, Els Wagenaar, Ellen Bolscher, Martina Novotna, Johan W. Jonker and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics January 1, 2005, 312 (1) 144-152; DOI: https://doi.org/10.1124/jpet.104.073916
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