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
| Autor: | Swati Rawat, Satori A. Marchitti, Christopher S. Mazur, Jason Zastre, Caleb M. Dillingham, Anshika Sharma, John F. Kenneke |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Abcg2 Metabolite Blotting Western Polybrominated Biphenyls ATP-binding cassette transporter 010501 environmental sciences Pharmacology Toxicology 01 natural sciences Article Gas Chromatography-Mass Spectrometry 03 medical and health sciences chemistry.chemical_compound Tandem Mass Spectrometry ATP Binding Cassette Transporter Subfamily G Member 2 Humans ATP Binding Cassette Transporter Subfamily B Member 1 0105 earth and related environmental sciences P-glycoprotein biology Chemistry Transporter Environmental Exposure Neoplasm Proteins 030104 developmental biology Biochemistry biology.protein Efflux Xenobiotic Intracellular Chromatography Liquid |
| Zdroj: | Toxicological Sciences. 155:270-282 |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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