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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Department of Pharmacology and Toxicology and Research Center, Charles University in Prague, Faculty of Pharmacy, Hradec Králové, the Czech Republic (P.P., M.N.); and Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands (G.M., E.W., E.B., J.W.J., A.H.S.)
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, 6
-methylprednisolone, dexamethasone, and triamcinolone) and 17
-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.
Address correspondence to: Alfred H. Schinkel, Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: a.schinkel{at}nki.nl
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