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Decabromobiphenyl (PBB-209) activates the aryl hydrocarbon receptor while decachlorobiphenyl (PCB-209) is inactive: experimental evidence and computational rationalization of the different behavior of some halogenated biphenyls

AutorAlonso Giner, Mercedes; Casado, Susana; Miranda, Carlos; Tarazona, José V.; Navas, José M.; Herradón García, Bernardo
Fecha de publicación1-mar-2008
EditorAmerican Chemical Society
CitaciónChemical Research in Toxicology 21(3): 643-658 (2008)
ResumenIn rat H4IIE cells permanently transfected with a luciferase gene under the control of AhR, incubation with PBB-209 led to a statistically significant increase of luminescence. In this system, PCB-209 only caused a small induction of luciferase activity. In a fish cell line, only PBB-209 was able to provoke an induction of ethoxyresorufin-O-deethylase activity. Ligand binding to the AhR was studied by means of a cell-free in vitro system in which the activation of AhR is very unlikely to occur without ligand binding. None of the biphenyls studied provoked any activation of AhR in this system. To rationalize the results and to get insight into the molecular mechanism of activation of AhR by PBB-209 as compared with PCB-209, a comprehensive computational study was carried out on these congeners as well as on PCB-126 and PCB-169, two potent AhR activators through ligand binding. The calculations include (i) conformational analysis and dipole moments of each conformer, (ii) aromaticity indices, (iii) molecular electrostatic potentials, (iv) quadrupole moments, (v) electronic and reactivity descriptors, and (vi) dissociation energies of C−Cl and C−Br bonds in model aromatic compounds. It was found that some molecular features of PBB-209, such as the electrostatic potential (EP) and EP-derived descriptors (Politzer’s parameters), indicate that PBB-209 is more similar to PCB-126 and PCB-169 than to PCB-209, which share quite similar geometries based on the substitution pattern. The similarity between PBB-209, PCB-126, and PCB-169 seems to hint that these three compounds can share, at least partially, similar mechanisms of activation of AhR. It is unquestionable that PCB-126 and PCB-169 directly bind AhR and PBB-209 does not. We hypothesize that there are several simultaneous mechanisms for activation of AhR, and the most active compounds act for more than one mechanism.
Descripción16 pages, 9 figures, 7 tables.-- PMID: 18311929 [PubMed].-- Printed version published Mar 17, 2008.
This work was taken in part from the projected Ph.D. thesis of M.A. and S.C.
Supporting information available: Cartesian coordinates of the optimized geometries of the minima and transition states, experimental and calculated bond lengths and dihedral angles, aromaticity indices, Politzer’s descriptors, results (MSEPs, reactivity descriptors, and BDEs) calculated at the B3LYP/6-31+G(d,p) theory for PBB-209, PCB-209, PCB-169, and PCB-126, and calculation of the quadrupole moment. Available at: http://pubs.acs.org/doi/suppl/10.1021/tx700362u/suppl_file/tx700362u-file003.pdf
Versión del editorhttp://dx.doi.org/10.1021/tx700362u
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