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Received for publication July 8, 2004.
Revised September 7, 2004.
Accepted for publication September 8, 2004.
The breast cancer resistance protein (BCRP/ABCG2) is an ATP binding cassette (ABC) drug efflux transporter that extrudes xenotoxins from cells, mediating drug resistance and affecting the pharmacological behaviour of many compounds. To study the interaction of human wild-type BCRP with steroid drugs, hormones and the dietary carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), 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). However, none of the tested endogenous steroids or synthetic glucocorticoids nor digoxin 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.
Key words:
ABC transporters, breast cancer resistance protein, carcinogens, cimetidine, glucocorticoids, steroid hormones
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