title: Inhibition of the Human ABC Efflux Transporters P-gp and BCRP by the BDE-47 Hydroxylated Metabolite 6-OH-BDE-47: Considerations for Human Exposure.
abstract: High body burdens of polybrominated diphenyl ethers (PBDEs) in infants and young children have led to increased concern over their potential impact on human development. PBDE exposure can alter the expression of genes involved in thyroid homeostasis, including those of ATP-binding cassette (ABC) transporters, which mediate cellular xenobiotic efflux. However, little information exists on how PBDEs interact with ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). The purpose of this study was to evaluate the interactions of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and its hydroxylated metabolite 6-OH-BDE-47 with P-gp and BCRP, using human MDR1- and BCRP-expressing membrane vesicles and stably transfected NIH-3T3-MDR1 and MDCK-BCRP cells. In P-gp membranes, BDE-47 did not affect P-gp activity; however, 6-OH-BDE-47 inhibited P-gp activity at low µM concentrations (IC50=11.7 µM). In BCRP membranes, BDE-47 inhibited BCRP activity; however, 6-OH-BDE-47 was a stronger inhibitor [IC50=45.9 µM (BDE-47) vs. IC50=9.4 µM (6-OH-BDE-47)]. Intracellular concentrations of known P-gp and BCRP substrates [(3H)-paclitaxel and (3H)-prazosin, respectively] were significantly higher (indicating less efflux) in NIH-3T3-MDR1 and MDCK-BCRP cells in the presence of 6-OH-BDE-47, but not BDE-47. Collectively, our results indicate that the BDE-47 metabolite 6-OH-BDE-47 is an inhibitor of both P-gp and BCRP efflux activity. These findings suggest that some effects previously attributed to BDE-47 in biological systems may actually be due to 6-OH-BDE-47. Considerations for human exposure are discussed.
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Athens, Georgia 30605.
authors.forename: Satori A
authors.initials: SA
authors.lastname: Marchitti
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Athens, Georgia 30605.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Mazur
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Athens, Georgia 30605.
authors.forename: Caleb M
authors.initials: CM
authors.lastname: Dillingham
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Athens, Georgia 30605.
authors.forename: Swati
authors.initials: S
authors.lastname: Rawat
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602.
authors.forename: Anshika
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602.
authors.forename: Jason
authors.initials: J
authors.lastname: Zastre
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Athens, Georgia 30605; kenneke.john@epa.gov.
authors.forename: John F
authors.initials: JF
authors.lastname: Kenneke
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D002853:Chromatography, Liquid; D004781:Environmental Exposure; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D053719:Tandem Mass Spectrometry
chemical_list: C580599:6-OH-BDE-47; C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D009363:Neoplasm Proteins; D011075:Polybrominated Biphenyls
keywords: ABC transporters; BCRP; MDR1; P-gp; brominated flame retardants; polybrominated diphenyl ethers (PBDEs).