MODULATION OF STEROID SULFONATION BY CELECOXIB-LIKE DRUGS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 体外研究表明，非甾体抗炎药塞来昔布能调节磺基转移酶SULT2A1、人肝细胞液[9]和制备中的手稿催化的17-雌二醇E_2和雌酮E_1硫酸酯的形成。对于这两种类固醇，在塞来昔布的存在下，3-硫酸盐代谢物的形成减少，而对于E2，3-硫酸盐的减少被17？x-硫酸盐的增加所平衡。E_2-17？x-硫酸盐通常是E_2的一种很小的代谢物。到目前为止，还没有研究确定塞来昔布对雌三醇E3磺化的影响，但我们预测3-磺化会减少。E1-3-硫酸盐和E2-3-硫酸盐与蛋白质高度结合，在血液中转运到对雌激素敏感的组织，包括乳房，在那里硫酸盐结合物被硫酸酯酶水解为游离雌激素。重要的是，E_2-17-硫酸盐对硫酸酯酶不敏感。这些发现导致了我们的假设，即要么塞来昔布本身，要么是一种对磺基转移酶有类似作用的待设计药物，通过限制乳房组织暴露于雌二醇，可能是一种有效的辅助治疗雌激素依赖型乳腺癌。GCRC研究的目的是确定塞来昔布是否改变了女性体内雌二醇、雌酮和雌三醇的代谢，这是通过这些类固醇和类固醇结合物的血清和尿液水平来衡量的。证明塞来昔布在体内和体外对雌激素硫化的影响对于证实我们的假说很重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The non-steroidal anti-inflammatory drug, celecoxib, has been shown through in vitro studies to modulate the formation of sulfate esters of 17¿x-estradiol E2 and estrone E1 catalyzed by the sulfotransferase enzyme, SULT2A1, as well as by human liver cytosol [9] and manuscript in preparation. For both steroids, formation of the 3-sulfate metabolite was decreased in the presence of celecoxib, and for E2 the decrease in 3-sulfation was balanced by an increase in 17¿x-sulfation. E2-17¿x-sulfate is normally a very minor metabolite of E2. As yet, no studies have been conducted to determine the effect of celecoxib on estriol E3 sulfonation, but we predict the 3-sulfation would be decreased. E1-3-sulfate and E2-3-sulfate are highly protein-bound and are transported in the blood to estrogen-sensitive tissues, including the breast, where the sulfate conjugates are hydrolyzed to the free estrogen by sulfatase. Of significance is that E2-17-sulfate is not susceptible to sulfatase. These finding have led to our hypothesis that either celecoxib itself, or a to-be-designed drug with similar effects on sulfotransferase, could be an effective adjunct treatment of estrogen-dependent breast cancer, by limiting the breast tissue exposure to estradiol. The purpose of the GCRC study is to determine if celecoxib alters the in vivo metabolism of estradiol, estrone and estriol in women, as measured by serum and urinary levels of these steroids and steroid conjugates. Demonstrating in vivo as well as in vitro effects of celecoxib on estrogen sulfation is important in substantiating our hypothesis.