MODULATION OF STEROID SULFONATION BY CELECOXIB-LIKE DRUGS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 体外研究显示，非甾体抗炎药塞来昔布可调节由磺基转移酶SULT 2A 1以及人肝胞质溶胶和制备中的手稿催化的17 β-雌二醇-E2和雌酮-E1硫酸酯的形成。 对于两种类固醇，塞来昔布存在时3-硫酸盐代谢产物的形成减少，对于E2，3-硫酸化的减少被17 β-硫酸化的增加所平衡。E2-17 β-硫酸盐通常是E2的一种非常次要的代谢产物。 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-硫酸化会减少。 E1-3-硫酸盐和E2-3-硫酸盐与蛋白质高度结合，并在血液中转运至雌激素敏感组织，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，E2-17-硫酸盐对硫酸酯酶不敏感。 这些发现使我们假设塞来昔布本身或对磺基转移酶具有类似作用的待设计药物可能通过限制乳腺组织暴露于雌二醇而成为雌激素依赖性乳腺癌的有效辅助治疗。 GCRC研究的目的是确定塞来昔布是否改变女性体内雌二醇、雌酮和雌三醇的代谢，通过测定这些类固醇和类固醇结合物的血清和尿液水平。 证明塞来昔布在体内和体外对雌激素硫酸化的影响对证实我们的假设很重要。

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 beta-estradiol-E2 and estrone-E1 catalyzed by the sulfotransferase enzyme, SULT2A1, as well as by human liver cytosol 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 beta-sulfation. E2-17 beta-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.