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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

Authors: Sueyoshi, Tatsuya; Li, Linhao; Wang, Hongbing; Moore, Rick; Kodavanti, Prasada Rao S; Lehmler, Hans-Joachim; Negishi, Masahiko; Birnbaum, Linda S

Published In Toxicol Sci, (2014 Feb)

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.

PubMed ID: 24218150 Exiting the NIEHS site

MeSH Terms: Animals; Blotting, Western; Cells, Cultured; Cytochrome P-450 Enzyme System/genetics; Endocrine Disruptors/toxicity*; Flame Retardants/toxicity*; Gene Expression/drug effects; Genes, Reporter; Halogenated Diphenyl Ethers/toxicity*; Hepatocytes/drug effects*; Hepatocytes/enzymology; Hepatocytes/metabolism; Humans; Mice; Mice, Knockout; Microsomes, Liver/drug effects; Microsomes, Liver/metabolism; Pregnane X Receptor; Primary Cell Culture; RNA, Messenger/genetics; RNA, Messenger/metabolism; Real-Time Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism*; Receptors, Steroid/genetics; Receptors, Steroid/metabolism; Transfection

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