Flame Retardant BDE-47 Effectively Activates Nuclear Receptor CAR in Human Primary Hepatocytes

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

doi:10.1093/toxsci/kft243

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Flame Retardant BDE-47 Effectively Activates Nuclear Receptor CAR in Human Primary Hepatocytes

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Flame Retardant BDE-47 Effectively Activates Nuclear Receptor CAR in Human Primary Hepatocytes

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

Toxicological sciences, Vol.137(2), pp.292-302

02/2014

DOI: 10.1093/toxsci/kft243

PMCID: PMC3908718

PMID: 24218150

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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 and CYP2B6 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.

PXR

CAR

PBDE

xenobiotic receptor

Synthesis Core

Details

Title: Subtitle: Flame Retardant BDE-47 Effectively Activates Nuclear Receptor CAR in Human Primary Hepatocytes
Creators: Tatsuya Sueyoshi - Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology
Linhao Li - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy
Hongbing Wang - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy
Rick Moore - Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology
Prasada Rao S Kodavanti - Neurotoxicology Branch, NHEERL/ORD, EPA, Research Triangle Park
Hans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, The University of Iowa
Masahiko Negishi - Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology
Linda S Birnbaum - Laboratory of Toxicokinetics, National Cancer Institute at NIHES, National Institute of Environmental Health Sciences, Research Triangle Park
Resource Type: Journal article
Publication Details: Toxicological sciences, Vol.137(2), pp.292-302
DOI: 10.1093/toxsci/kft243
PMID: 24218150
PMCID: PMC3908718
NLM abbreviation: Toxicol Sci
ISSN: 1096-6080
eISSN: 1096-0929
Publisher: Oxford University Press; US
Language: English
Date published: 02/2014
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
Record Identifier: 9984000933702771

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