MODULATION OF STEROID SULFONATION BY CELECOXIB-LIKE DRUGS

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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.