title: The widely utilized brominated flame retardant tetrabromobisphenol A (TBBPA) is a potent inhibitor of the SERCA Ca2+ pump.
abstract: TBBPA (tetrabromobisphenol A) is currently the most widely used type of BFR (brominated flame retardant) employed to reduce the combustibility of a large variety of electronic and other manufactured products. Recent studies have indicated that BFRs, including TBBPA, are bio-accumulating within animal and humans. BFRs including TBBPA have also been shown to be cytotoxic and potentially endocrine-disrupting to a variety of cells in culture. Furthermore, TBBPA has specifically been shown to cause disruption of Ca2+ homoeostasis within cells, which may be the underlying cause of its cytotoxicity. In this study, we have demonstrated that TBBPA is a potent non-isoform-specific inhibitor of the SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) (apparent K(i) 0.46-2.3 microM), thus we propose that TBBPA inhibition of SERCA contributes in some degree to Ca2+ signalling disruption. TBBPA binds directly to the SERCA without the need to partition into the phospholipid bilayer. From activity results and Ca2+-induced conformational results, it appears that the major effect of TBBPA is to decrease the SERCA affinity for Ca2+ (increasing the K(d) from approx. 1 microM to 30 microM in the presence of 10 microM TBBPA). Low concentrations of TBBPA can quench the tryptophan fluorescence of the SERCA and this quenching can be reversed by BHQ [2,5-di-(t-butyl)-1,4-hydroquinone] and 4-n-nonylphenol, but not thapsigargin, indicating that TBBPA and BHQ may be binding to similar regions in the SERCA.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Oluseye A
authors.initials: OA
authors.lastname: Ogunbayo
authors.forename: Francesco
authors.initials: F
authors.lastname: Michelangeli
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005411:Flame Retardants / Q000494:pharmacology*; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010766:Phosphorylation; D011075:Polybrominated Biphenyls / Q000494:pharmacology*; D011487:Protein Conformation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*