title: New brominated flame retardants and their metabolites as activators of the pregnane X receptor.
abstract: 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 PPARα and PPARγ 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 5.5μM for TBPH and 2.0μM 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, 13.9μM). 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.
authors: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors: Darja
authors: D
authors: Gramec Skledar
authors: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors: Tihomir
authors: T
authors: Tomašič
authors: University of Perugia, Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina e Chirurgia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Adriana
authors: A
authors: Carino
authors: University of Perugia, Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina e Chirurgia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Eleonora
authors: E
authors: Distrutti
authors: University of Perugia, Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina e Chirurgia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors: Stefano
authors: S
authors: Fiorucci
authors: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia. Electronic address: lucija.peterlin@ffa.uni-lj.si.
authors: Lucija
authors: L
authors: Peterlin Mašič
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001665:Binding Sites; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005411:Flame Retardants / Q000032:analysis / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010795:Phthalic Acids / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000077297:Pregnane X Receptor; D011487:Protein Conformation; D011987:Receptors, Steroid / Q000819:agonists*
chemical_list: C576261:2-ethylhexyl 2,3,4,5-tetrabromobenzoate; D001565:Benzoates; D005411:Flame Retardants; D047493:PPAR alpha; D047495:PPAR gamma; D010795:Phthalic Acids; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C576262:bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate; D051544:Cytochrome P-450 CYP3A
keywords: Pregnane X receptor; TBB; TBPH; brominated flame retardants; metabolites