We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- 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.
- Authors
Marchitti, Satori A.; Mazur, Christopher S.; Dillingham, Caleb M.; Rawat, Swati; Sharma, Anshika; Zastre, Jason; Kenneke, John F.
- 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 2,20,4,40-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.
- Subjects
EFFLUX (Microbiology); POLYBROMINATED diphenyl ethers; ATP-binding cassette transporters; XENOBIOTICS; HOMEOSTASIS; GLYCOPROTEINS
- Publication
Toxicological Sciences, 2017, Vol 155, Issue 1, p270
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kfw209