抗雌激素的DNA三苯氧胺引起的破坏性影响和toremifene代谢物。

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刘X, Pisha E, Tonetti哒,姚明D,李Y,姚明J, Burdette我,博尔顿杰

抗雌激素的DNA三苯氧胺引起的破坏性影响和toremifene代谢物。

化学Res Toxicol。2003年7月,16 (7):832 - 7。

PubMed ID

12870885 (在PubMed

]

文摘

抗雌激素,它莫西芬,已广泛应用于乳腺癌的治疗和预防。尽管它莫西芬显示优点在乳腺癌的化疗和化学预防,流行病学研究服用它莫西芬在乳腺癌患者和健康女性表示,治疗引起的增加患子宫内膜癌的风险。这些令人不安的副作用导致担忧长期安全的药物。因此,重要的是要完全理解抗雌激素的之间的关系和三苯氧胺的基因毒性机制,其他抗雌激素及其代谢物。以前,我们已经表明,邻醌三苯氧胺及其类似物形成,droloxifene 4-hydroxytoremifene,不得这些抗雌激素导致的细胞毒性效应;然而,这些邻醌与deoxynucleosides可以形成加合物,这意味着邻醌通路可能导致体内抗雌激素的基因毒性。进一步研究这种潜在的基因毒性通路,我们感兴趣的雌激素受体(ER)的作用(1)以来的α和β与儿茶酚雌激素已经表明,人似乎加强乳腺癌细胞系的DNA损伤。因此,我们调查了绑定的4-hydroxy和3上的相似之处,4-dihydroxy衍生品的他莫昔芬和toremifene ERα和β。使用石川细胞的代谢产物的抗雌激素的活动也ERalpha调查以及他们的活动和ERbeta乳腺癌细胞使用瞬时转染记者,雌激素响应element-dependent荧光素酶检测。数据显示,这些化合物的抗雌激素的活动在生物分析模仿他们的活动在ER绑定化验。 To determine if the compounds were toxic and if ERs played a role in this process, the cytotoxicity of these compounds in ERbeta41(2) (ERbeta), S30 (ERalpha), and MDA-MB-231 (ER(-)) cell lines was compared. The results showed that the cytotoxicity differences between the metabolites were modest. In addition, all of the metabolites showed similar toxicity patterns in both ER positive and negative cell lines, which means that the ER may not contribute to the cytotoxicity pathway. Finally, we compared the amount of DNA damage induced by these metabolites in these cell lines using the comet assay. The catechols 3,4-dihydroxytoremifene and 3,4-dihydroxytamoxifen induced a greater amount of cellular single strand DNA cleavage as compared with the phenols in all cell lines. The different amounts of DNA damage in ER positive and negative cell lines suggested that the ERs might play a role in this process. These data suggest that the formation of catechols represents a minor role in cytotoxic and antiestrogenic effects in cells as compared with their phenol analogues. However, catechols induced more DNA damage at nontoxic doses in breast cancer cells, which implies that o-quinones formed from catechols could contribute to genotoxicity in vivo, which is ER-dependent.

DrugBank数据引用了这篇文章

药物靶点

药物	目标	类	生物	药理作用	行动
Toremifene	雌激素受体α	蛋白质	人类	是的	调制器	细节