Structure-dependent activation of peroxisome proliferator-activated receptor (PPAR) γ by organotin compounds
Structure-dependent activation of peroxisome proliferator-activated receptor (PPAR) γ by organotin compounds
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DOI：
10.1016/j.cbi.2009.03.006
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发表时间：
2009-07-15
影响因子：
5.1
通讯作者：
Nakanishi, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Hiromori, Youhei;Nishikawa, Jun-ichi;Nakanishi, Tsuyoshi
有机锡化合物，如三丁基锡（TBT）和三苯基锡（TPT）是常见的环境污染物，并被怀疑干扰脊椎动物和无脊椎动物的内分泌功能。以前，我们报道，TBT和TPT的功能作为过氧化物酶体增殖物激活受体（PPAR）γ的强大激动剂，并刺激脂肪细胞分化通过PPAR γ信号通路。我们目前的研究调查的结构依赖性结合的丁基锡和苯基锡化合物的过氧化物酶体增殖物激活受体γ和他们的能力。用纯化的重组PPARy进行的Scatchard分析表明，[C-14]TPT以66.6 +/-5.2nM的平衡解离常数（K-d）结合PPARy，其接近典型的PPARy激动剂[H-3]罗格列酮（Rosi）的46.2 +/-2.5nM K-d。和四丁基锡（TeBT）以竞争性方式阻断[H-3]Rosi与PPAR γ的结合，除一丁基锡外，所有测试的有机锡化合物均以竞争性方式阻断[C-14]TPT与PPAR γ的结合。出乎意料的是，Rosi完全不与[C-14]TPT竞争结合至PPAR γ，并且与竞争测定的结果相反，TBT和TeBT而不是二丁基锡转录激活GAL-PPAR γ嵌合受体。所有测试的苯基锡化合物都以TPT> DPT>单苯基锡的效力顺序转录激活GAL-PPAR γ。此外，用TBT、TeBT和所有测试的苯锡化合物处理人绒毛膜癌细胞都会刺激人绒毛膜促性腺激素的产生，而人绒毛膜促性腺激素的产生是通过PPAR γ介导的转录上调的。我们的观察表明，三烷基化和三苯基化锡化合物是最有效的PPAR γ激动剂的烷基化和苯基化的锡化合物。并且锡原子上的苯基取代基比丁基取代基更能增强有机锡化合物作为PPAR γ激动剂的效力。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
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.