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

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) gamma and stimulate adipocyte differentiation via the PPAR gamma signaling pathway. Our current study investigates the structure-dependent binding of butyltin and phenyltin compounds to PPAR gamma and their ability to activate the receptor. A Scatchard analysis with purified recombinant PPAR gamma demonstrated that [C-14]TPT binds to PPAR gamma 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 PPAR gamma agonist, [H-3] rosiglitazone (Rosi).TBT, TPT, diphenyltin (DPT), and tetrabutyltin (TeBT) blocked the binding of [H-3]Rosi to PPAR gamma in a competitive manner, and all tested organotin compounds except monobutyltin blocked the binding of [C-14]TPT to PPAR gamma in a competitive manner. Unexpectedly, Rosi did not compete at all with [C-14]TPT for binding to PPAR gamma, and contrary to the results of the competition assay, TBT and TeBT, but not dibutyltin, transcriptionally activated a GAL-PPAR gamma chimeric receptor. All tested phenyltin compounds transcriptionally activated GAL-PPAR gamma 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 PPAR gamma-mediated transcription. Our observations indicate that trialkylated and triphenylated tin compounds are the most potent PPAR gamma agonists among the alkylated and phenylated tin compounds. and a phenyl substituent on a tin atom enhances the potency of organotin compounds as a PPAR gamma agonist much more than a butyl substituent. (C) 2009 Elsevier Ireland Ltd. All rights reserved.