Molecular Mechanisms of Environmental Organotin Toxicity in Mammals
Molecular Mechanisms of Environmental Organotin Toxicity in Mammals
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DOI：
10.1248/bpb.b212017
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发表时间：
2012-11-01
影响因子：
2
通讯作者：
Kotake, Yaichiro
中科院分区：
文献类型：
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作者：
Kotake, Yaichiro
三丁基锡等有机锡除了具有干扰内分泌的功能外，还被怀疑对哺乳动物具有多种毒性作用。人体血液中的内源性有机锡浓度范围从几nM到几百nM。本文综述了三丁基锡（TBT）和三苯基锡（TPT）等环境有机锡化合物对哺乳动物的毒性机制。TBT和TPT是线粒体ATP合酶的有效抑制剂，最近的一项研究表明，TBT直接与ATP合酶结合。有机锡干扰类固醇的生物合成和降解。三丁基锡化合物和三丁基锡化合物是类维生素A X受体（RXR）和过氧化物酶体增殖物激活受体γ（PPAR γ）的双重激动剂;它们还可能通过激活过氧化物酶体增殖物激活受体γ在体外和体内诱导脂肪细胞分化，这表明它们可能具有致肥胖作用。环境中的有机锡也具有神经毒性;它们会导致行为异常，并对发育中的中枢神经系统有毒。体外研究表明，有机锡诱导细胞内钙离子升高和谷氨酸兴奋毒性。最近，据报道，内源性三丁基锡化合物水平降低2-氨基-3-（5-甲基-3-氧代-1，2-恶唑-4-基）丙酸（AMPA）受体亚单位GluR 2的表达，导致神经元的脆弱性。大多数的实验研究采用有机锡在浓度的PM顺序，它仍然是重要的是澄清内源性水平的环境有机锡诱导的事件的分子机制。
Organotins such as tributyltin are suspected of having multiple toxic effects in mammals, in addition to their endocrine-disrupting function. Endogenous organotin concentrations in human blood range from a few to a few hundred nM. In this review, we summarize recent findings on the mechanisms of toxicity of environmental organotins such as tributyltin (TBT) and triphenyltin (TPT) in mammals. TBT and TPT are potent inhibitors of mitochondrial ATP synthase, and a recent study suggests that TBT binds directly to ATP synthase. Organotins disturb steroid biosynthesis and degradation. TBT and TPT are dual agonists of retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPAR gamma); they also induce the differentiation of adipocytes in vitro and in vivo, probably through PPAR gamma activation, suggesting that they may work as obesogens. Environmental organotins are also neurotoxic; they induce behavioral abnormality and are toxic to the developing central nervous system. In vitro studies have shown that organotins induce intracellular Ca2+ elevation and glutamate excitotoxicity. Recently, it was reported that endogenous levels of TBT decrease expression of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor subunit GluR2, leading to neuronal vulnerability. Most of the experimental studies have employed organotins at concentrations of pm order, and it remains important to clarify the molecular mechanisms of events induced by endogenous levels of environmental organotins.