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.

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, 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.

• Authors: Petr Pavek, Gracia Merino, Els Wagenaar, Ellen Bolscher, Martina Novotna, Johan W Jonker, Alfred H Schinkel
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 312 Issue 1 Pg. 144-52 (Jan 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15365089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Hormones
• Imidazoles
• Neoplasm Proteins
• Receptors, Histamine H2
• Steroids
• Aldosterone
• Cimetidine
• 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Aldosterone (pharmacology)
• Animals
• Biological Transport
• Cell Line
• Cimetidine (pharmacology)
• Hormones (metabolism)
• Humans
• Imidazoles (pharmacology)
• Mice
• Neoplasm Proteins (metabolism)
• Receptors, Histamine H2 (metabolism)
• Steroids (pharmacology)