@article{ref1,
title="Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes",
journal="Toxicological sciences",
year="2014",
author="Negishi, Masahiko and Lehmler, Hans-Joachim and Kodavanti, Prasada Rao S. and Moore, Rick and Wang, Hongbing and Birnbaum, Linda S. and Li, Linhao and Sueyoshi, Tatsuya",
volume="137",
number="2",
pages="292-302",
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 PXR (pregnane X receptor) 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.<p /> <p>Language: en</p>",
language="en",
issn="1096-6080",
doi="10.1093/toxsci/kft243",
url="http://dx.doi.org/10.1093/toxsci/kft243"
}