Citation

Sueyoshi T, Li L, Wang H, Moore R, Kodavanti PR, Lehmler HJ, Negishi M, Birnbaum LS. Toxicol. Sci. 2014; 137(2): 292-302.

Affiliation

Pharmacogenetics section, Laboratory of Reproductive and Developmental Toxicology, Research Triangle Park, NC 27709.

Copyright

(Copyright © 2014, Oxford University Press)

DOI

10.1093/toxsci/kft243

PMID

24218150

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.

Language: en