Organotins disrupt the 11beta-hydroxysteroid dehydrogenase type 2-dependent local inactivation of glucocorticoids.
Organotins disrupt the 11beta-hydroxysteroid dehydrogenase type 2-dependent local inactivation of glucocorticoids.
复制标题
有机素破坏了11beta-羟基甾体脱氢酶2型糖皮质激素的局部失活。
DOI：
10.1289/ehp.8209
复制
发表时间：
2005-11
影响因子：
10.4
通讯作者：
Odermatt, Alex
中科院分区：
文献类型：
--
作者：
Atanasov, Atanas G;Nashev, Lyubomir G;Tam, Steven;Baker, Michael E;Odermatt, Alex
有机砷是重要的环境污染物，广泛应用于农业和工业领域，在食物链中积累，在一些海洋物种中引起性行为，并对高等动物产生神经毒性和免疫毒性作用。在接触有机激素后观察到的出生体重减轻和胸腺退化，也可能是由于糖皮质激素水平过高引起的。我们现在证明有机素有效地抑制11β-羟基类固醇脱氢酶2型（11β-HSD2），将活性11β-羟基糖皮质激素转化为非活性11-酮糖皮质激素，而不是催化逆反应的11β-HSD1。二苯基锡和三苯基锡以及二苯基锡和三苯基锡在裂解物和完整细胞中抑制重组和内源性11β-HSD2， IC50值在500 nM和3 μM之间。二硫苏糖醇保护11β-HSD2免受有机锡依赖性抑制，表明有机锡通过与一种或多种半胱氨酸结合而起作用。突变分析和三维结构建模揭示了11β-HSD2中几个重要的半胱氨酸相互作用。Cys90、Cys228和Cys264对酶的稳定性和催化活性至关重要，这表明有机tin破坏这些相互作用导致11β-HSD2的抑制。由于11β-HSD2功能的破坏，糖皮质激素浓度的增加可能有助于在一些糖皮质激素敏感组织（如胸腺和胎盘）中观察到的有机锡依赖性毒性。
Organotins, important environmental pollutants widely used in agricultural and industrial applications, accumulate in the food chain and induce imposex in several marine species as well as neurotoxic and immunotoxic effects in higher animals. Reduced birth weight and thymus involution, observed upon exposure to organotins, can also be caused by excessive glucocorticoid levels. We now demonstrate that organotins efficiently inhibit 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), converting active 11β-hydroxyglucocorticoids into inactive 11-ketoglucocorticoids, but not 11β-HSD1, which catalyzes the reverse reaction. Di- and tributyltin as well as di- and triphenyltin inhibited recombinant and endogenous 11β-HSD2 in lysates and intact cells with IC50 values between 500 nM and 3 μM. Dithiothreitol protected 11β-HSD2 from organotin-dependent inhibition, indicating that organotins act by binding to one or more cysteines. Mutational analysis and 3-D structural modeling revealed several important interactions of cysteines in 11β-HSD2. Cys90, Cys228, and Cys264 were essential for enzymatic stability and catalytic activity, suggesting that disruption of such interactions by organotins leads to inhibition of 11β-HSD2. Enhanced glucocorticoid concentrations due to disruption of 11β-HSD2 function may contribute to the observed organotin-dependent toxicity in some glucocorticoid-sensitive tissues such as thymus and placenta.
DOI：
10.1083/jcb.50.3.583
发表时间：
1971-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
La Pushin RW;de Harven E
通讯作者：
de Harven E