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Estrone sulfate
Estrone-14C and estrone sulfate-3H were simultaneously injected into a 37-yr-old woman and disposition of the two isotopes was followed. The products of estrone sulfate were excreted in urine more rapidly and to a greater extent than those of the coadministered estrone. Estrone was converted to estrone and estradiol glucuronides to a much greater extent than its sulfate conjugate. Estrone sulfate on the other hand contributed more to the urinary estrone and estradiol sulfates. All of the other metabolites irrespective of their conjugation contained equal amounts of both isotopes and were therefore most probably biosynthesized after equilibration of the dose. It is likely that estrone sulfate rather than estrone is the precursor of these compounds.
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Abstract Concentrations of estradiol in human breast tumors from pre‐ and post‐menopausal women are similar whereas plasma levels are 5‐ to 60‐fold lower in post‐menopausal women. The mechanism for maintaining high tumor tissue estrogen levels in post‐menopausal women is unknown but could be related to the ability of plasma estrone sulfate to serve as a precursor for estradiol synthesis in tumor tissue. Estrone sulfate plasma levels are 30‐fold higher than free estradiol levels in postmenopausal women and estrone sulfatase is present in many tissues, including breast tumors, supporting this hypothesis. In this study, we examined the ability of exogenously administered estrone sulfate to stimulate growth of a carcinogeninduced, hormone‐dependent rat mammary tumor and measured the rate of conversion of estrone sulfate to free estrone and estradiol. Castrate rats bearing nitrosomethylurea‐induced mammary tumors were infused with estradiol as a control or estrone sulfate over a 14‐day period. Estradiol at low doses significantly increased tumor volume whereas higher amounts paradoxically inhibited growth. By comparison, estrone sulfate infusions significantly increased tumor volume over that observed in castrate animals on both days 7 and I4 of infusion. To determine whether estrone sulfate was converted to free estrone and estradiol during this protocol, 3 H‐estrone sulfate was substituted for unlabelled steroid and castrate animals were again infused for 14 days. At 7, 10 and 14 days of infusion, 18‐26% of estrone sulfate was converted to free estrone and 9‐16% to free estradiol. There were no significant differences between the 2 doses used and the rates of conversion were stable over the infusion period. Conversion of estrone sulfate to free estradiol was also demonstrated by radioimmunoassay of free estradiol in plasma during estrone sulfate infusions. These data demonstrate that exogenously administered estrone sulfate can stimulate mammary tumor growth in castrate animals and support the possibility that estrone sulfate may serve as an important source of tumor tissue estradiol.
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Although circulating estrone-3-sulfate is a major precursor of biologically active estrogen, permeation across the plasma membrane is unlikely to occur by diffusion because of the high hydrophilicity of the molecule. The object of this study was to clarify the involvement of specific transporter(s) in the supply of estrone-3-sulfate to human breast cancer-derived T-47D cells, which grow in an estrogen-dependent manner. The proliferation of T-47D cells was increased by the addition of estrone-3-sulfate, or estradiol, to the cultivation medium. The initial uptake rate of estrone-3-sulfate kinetically exhibited a single saturable component, with Km and Vmax values of 7.6 μM and 172 pmol/mg of protein/min, respectively. The replacement of extracellular Na+ with Li+, K+, or N-methylglucamine+ had no effect on the uptake of [3H]estrone-3-sulfate. The uptake was strongly inhibited by sulfate conjugates of steroid hormones, but not by estradiol-17β-glucuronide. Taurocholate and sulfobromophthalein inhibited the uptake, whereas other tested anionic and cationic compounds did not. The expression of organic anion transporting polypeptides, OATP-D and OATP-E, which are candidate transporters of estrone-3-sulfate, was detected by reverse transcription-polymerase chain reaction analysis, although their actual involvement in the uptake of estrogen remains to be clarified. In conclusion, the uptake of estrone-3-sulfate by T-47D cells was mediated by a carrier-mediated transport mechanism, suggesting that the estrogen precursor is actively imported by estrogen-dependent breast cancer cells.
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