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New brominated flame retardants and their metabolites as activators of the pregnane X receptorGramec, Darja, farmacevtka ...The present study investigated the activities on different nuclear receptors of the new brominated flame retardants 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (TBB) and bis(2-ethylhexyl) ... 2,3,4,5-tetrabromophthalate (TBPH), and their main carboxylic acid metabolites 2,3,4,5-tetrabromobenzoic acid (TBBA) and mono(2-ethylhexyl) tetrabromophthalate (TBMEPH). None of selected chemicals exhibited marked activity towards PPAR alpha and PPAR gamma by the use of transactivation assays in HepG2 cells transfected with peroxisome proliferator-activated receptors. In contrast, selected flame retardants all exhibited potent agonist activity on pregnane X receptor (PXR), with EC50 values of 5.5microM for TBPH and 2.0microM for its metabolite TBMEPH. Molecular docking of TBPH and TBMEPH to the PXR ligand binding site revealed similar interactions, with differences only for conformation and orientation of the alkyl chains. Additionally, TBPH showed antagonist activity on PXR (IC50, 13.9microM). Moreover, there was significant up-regulation of CYP3A4 expression via PXR activation for TBB and TBPH and their metabolites. Induction of CYP3A4 might cause undesired drug-drug interactions, lower bioavailability of pharmaceutical drugs, higher formation of reactive toxic metabolites, or enhanced elimination of endogenous hormones, such as T3/T4, to lead to endocrine disruption. These data provide new and important insights into the toxicity of these new polybrominated flame retardants, TBB and TBPH, and their metabolites.Source: Toxicology letters. - ISSN 0378-4274 (Vol. 259, 2016, str. 116-123)Type of material - article, component part ; adult, seriousPublish date - 2016Language - englishCOBISS.SI-ID - 4142961
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Gramec, Darja, farmacevtka | 35432 |
Tomašič, Tihomir | 28334 |
Carino, Adriana | |
Distrutti, Eleonora | |
Fiorucci, Stefano | |
Peterlin-Mašič, Lucija | 19317 |
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