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Toxicol Sci. 2014 Feb;137(2):292-302. doi: 10.1093/toxsci/kft243. Epub 2013 Nov 11.

Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes.

Author information

1
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology and.

Abstract

Polybrominated diphenyl ether BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) is a thyroid hormone disruptor in mice; hepatic induction of various metabolic enzymes and transporters has been suggested as the mechanism for this disruption. Utilizing Car (-/-) and Pxr (-/-) mice as well as human primary hepatocytes, here we have demonstrated that BDE-47 activated both mouse and human nuclear receptor constitutive activated/androstane receptor (CAR). In mouse livers, CAR, not PXR, was responsible for Cyp2b10 mRNA induction by BDE-47. In human primary hepatocytes, BDE-47 was able to induce translocation of YFP-tagged human CAR from the cytoplasm to the nucleus andCYP2B6 and CYP3A4 mRNAs expressions. BDE-47 activated human CAR in a manner akin to the human CAR ligand CITCO (6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) in luciferase-reporter assays using Huh-7 cells. In contrast, mouse CAR was not potently activated by BDE-47 in the same reporter assays. Furthermore, human pregnane X receptor (PXR) was effectively activated by BDE-47 while mouse PXR was weakly activated in luciferase-reporter assays. Our results indicate that BDE-47 induces CYP genes through activation of human CAR in addition to the previously identified pathway through human PXR.

KEYWORDS:

CAR; PBDE; PXR; xenobiotic receptor.

PMID:
24218150
PMCID:
PMC3908718
DOI:
10.1093/toxsci/kft243
[Indexed for MEDLINE]
Free PMC Article

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