Structure-dependent activation of peroxisome proliferator-activated receptor (PPAR) γ by organotin compounds

Abstract

Organotin compounds such as tributyltin (TBT) and triphenyltin (TPT) are frequent environmental contaminants and are suspected of disrupting endocrine function in vertebrates and invertebrates. Previously, we reported that TBT and TPT function as powerful agonists for peroxisome proliferator-activated receptor (PPAR) γ and stimulate adipocyte differentiation via the PPARγ signaling pathway. Our current study investigates the structure-dependent binding of butyltin and phenyltin compounds to PPARγ and their ability to activate the receptor. A Scatchard analysis with purified recombinant PPARγ demonstrated that [ 14C]TPT binds to PPARγ with an equilibrium dissociation constant ( K d ) of 66.6 ± 5.2 nM, which approximated the 46.2 ± 2.5 nM K d of a typical PPARγ agonist, [ 3H]rosiglitazone (Rosi). TBT, TPT, diphenyltin (DPT), and tetrabutyltin (TeBT) blocked the binding of [ 3H]Rosi to PPARγ in a competitive manner, and all tested organotin compounds except monobutyltin blocked the binding of [ 14C]TPT to PPARγ in a competitive manner. Unexpectedly, Rosi did not compete at all with [ 14C]TPT for binding to PPARγ, and contrary to the results of the competition assay, TBT and TeBT, but not dibutyltin, transcriptionally activated a GAL–PPARγ chimeric receptor. All tested phenyltin compounds transcriptionally activated GAL–PPARγ with an order of potency of TPT > DPT > monophenyltin. In addition, treatment of human choriocarcinoma cells with TBT, TeBT, and all tested phenyltin compounds stimulated production of human chorionic gonadotropin, which is upregulated by PPARγ-mediated transcription. Our observations indicate that trialkylated and triphenylated tin compounds are the most potent PPARγ agonists among the alkylated and phenylated tin compounds, and a phenyl substituent on a tin atom enhances the potency of organotin compounds as a PPARγ agonist much more than a butyl substituent.