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.
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, 6alpha-methylprednisolone, dexamethasone, and triamcinolone) and 17beta-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 H(2)-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.
Pavek
Petr
P
Department of Pharmacology and Toxicology and Research Center, Charles University in Prague, Faculty of Pharmacy, Hradec, Králové, the Czech Republic.
Merino
Gracia
G
Wagenaar
Els
E
Bolscher
Ellen
E
Novotna
Martina
M
Jonker
Johan W
JW
Schinkel
Alfred H
AH
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002927:Cimetidine / Q000494:pharmacology*; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D006728:Hormones; D007093:Imidazoles; D009363:Neoplasm Proteins; D011970:Receptors, Histamine H2; D013256:Steroids; D000450:Aldosterone; D002927:Cimetidine; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine