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At least 19 recordsLinked to original sources
PubMed1995

Estrogenicity, antiestrogenicity and estrone sulfatase inhibition of estrone-3-amine and estrone-3-thiol.

Estrogen levels in breast tumors of post-menopausal women are at least 10 times higher than estrogen levels in plasma. The high level of estrogen in these tumors is postulated to be due to in situ formation of estrogen, possibly through conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Thus, inhibitors of estrone sulfatase are potential agents for the treatment of hormone-dependent breast cancers. We designed and synthesized a series of estra-1,3,5(10)triene-17-one, 3-amino and estra-1,3,5(10)triene-17-one, 3-thio derivatives. We have shown previously that several of these compounds substantially inhibit estrone sulfatase, exceeding Danazol in their inhibitory activity. However, little is known about the metabolism of these compounds and the possible effects of their metabolites in vivo. Two probable metabolites of the synthetic estrone analogs are estra-1,3,5(10)triene-17-one, 3-amine (E1-NH2), and estra-1,3,5(10)triene-17-one, 3-thiol (E1-SH). We tested these two compounds for estrogenicity, antiestrogenicity and inhibition of estrone sulfatase activity using a combination of in vivo and in vitro assays. The ovariectomized rat uterine weight gain assay was used to test for estrogenicity. Neither E1-NH2 nor E1-SH were estrogenic, as indicated by a lack of uterine weight gain when given at 25 micrograms/day for 7 days. The test compounds also were not antiestrogenic, in that they did not block estrone-induced uterine weight gain when given (100 micrograms/day) simultaneously with estrone (2 micrograms/day). Both compounds showed low affinity for the estrogen receptor. Using rat uterine cytosol as a source of estrogen receptor, the compounds displaced only a small percentage of [3H]estradiol binding, even when present at 1000-fold excess. Inhibition of estrone sulfatase activity was tested using human placental microsomes as a source of estrone sulfatase. E1-NH2 and E1SH showed very low levels of estrone sulfatase inhibition (15.1 and 9.8%, respectively) under conditions where Danazol showed more than 60% inhibition. Our results indicate that neither of these two compounds would present significant problems if they were the primary metabolite in a treatment involving estrone sulfatase inhibition of estrogen-dependent breast cancer.

Animals↗
PubMed1993

Transformation of estrone, estradiol, and estrone sulfate in uterine and vaginal isolated cells of fetal guinea pig. Effect of various antiestrogens in the conversion of estrone sulfate to estradiol.

The metabolism of physiological concentrations (5 x 10(-9) M) of [3H]estrone (E1), [3H]estradiol (E2), and [3H]estrone sulfate (E1S) was studied in isolated fetal uterine and vaginal cells of guinea pigs in culture. After 24 hours of incubation in both cells, a large percentage (40-60%) of E1 is converted to E2; however, after incubation of E2, most of the radioactive material (45-65%) corresponds to unchanged E2. Similarly, in the incubation medium the concentration of E2 is significantly higher related to E1 after incubation with E1 or E2. An intense sulfotransferase activity is found for both estrogens, whereas in the culture medium the respective sulfates represent 27-45% of the total radioactive material after incubation with the uterine cells and 15-24% for the vaginal cells. Using E1S, significant hydrolysis is observed in both cells and the analysis of the freed radioactive material indicated a high percentage in E2 (66% in the uterine cells and 71% in the vaginal cells). The conversion of E1S to E2 was strongly decreased by the antiestrogens: tamoxifen, 4-hydroxy-tamoxifen, and ICI 164,384. The inhibitory effect in relation to the incubation with E1S only was 43-66% in the uterine cells and 50-85% in the vaginal cells. The present data suggest that estrogen sulfates can play an important biological role in the target tissues of the fetus, and that the enzymatic mechanisms of the bioavailability of E2 for the biological responses of the hormone can be operated in the target tissue itself.

Animals↗
PubMed1999

Leptin enhances the synthesis of oleoyl-estrone from estrone in white adipose tissue.

BACKGROUND: Oleoyl-estrone elicits powerful slimming effects on lean and obese rats, sparing protein, lowering appetite and maintaining energy expenditure. Leptin synthesis is markedly reduced by oleoyl-estrone. However, this effect is not observed in the obese Zucker fa/fa rats; these rats do not fully respond to leptin but they lose fat under oleoyl-estrone treatment. AIM OF THE STUDY: To determine the role of leptin in the conversion of estrone to fatty-acyl estrone in white adipose tissue both in vivo in Zucker lean and obese rats, and in vitro. METHODS: Two series of experiments were performed: a) Growth and differentiation of 3T3L1 preadipocytes into adipocytes followed by incubation with tritium-labeled estrone in the medium in the presence/absence of 1 nM leptin, and estimation of the incorporation of label into estrone and estrone ester fractions of cell extracts. b) Zucker lean (Fa/?) [ZL] and obese (fa/fa) [ZO] rats were injected i.v. with carrier-free oleoyl-estrone in chylomicra-sized liposomes, then euthanized after 10 min. Free and esterified estrone were measured in blood, liver, muscle, skin, white adipose tissue (WAT), and brown adipose tissue (BAT). RESULTS: In the first study, in a 72-h incubation, adipocytes took up 20-27% of the medium estrone. In the leptin(-) controls, 47% of the label in the cell fraction was in the form of estrone esters and 45% as free estrone; in the leptin(+) cells, 71% of the label was in the estrone ester fraction and 24% was free estrone. In the second study, a large part of the injected tritium-label remained in the ZO blood, with only a small part remaining in ZL. In ZL 39% of the label was found in the tissues in the form of free estrone, and in ZO only 22%; in both cases about half of it was in WAT. Plasma free estrone levels were 0.3 +/- 0.1 nM in ZL and 0.5 +/- 0.3 nM in ZO, and esterified estrone was 242 +/- 99 nM for ZL and 201 +/- 29 nM for ZO. Plasma leptin levels were 1.73 +/- 0.16 ng/ml in ZL and 61.0 +/- 1.4 ng/ml in ZO. CONCLUSION: The presence of an infact leptin pathway is critical for the uptake and synthesis of estrone esters as well as for the plasma acyl-estrone turnover. The presented results show a direct relationship between oleoyl-estrone and leptin in the WAT. A fully functional leptin pathway is needed for the synthesis of acyl-estrone and the removal of free estrone from the bloodstream, as well as for the disposal of excess circulating oleoyl-estrone. This has a direct bearing on human and animal obesity, since estrone induces increases in fat deposition.

3T3 Cells↗
PubMed1996

Inhibition of placental estrone sulfatase activity and MCF-7 breast cancer cell proliferation by estrone-3-amino derivatives.

Estrogen levels in breast tumors of post-menopausal women are as much as 10 times higher than in plasma, presumably due to in situ formation of estrogen. Several lines of evidence indicate that the major source of estrogen in breast cancer cells may be from conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Inhibitors of estrone sulfatase may thus be potential agents for the treatment of estrogen-dependent breast cancer. We designed and synthesized a series of estrone-3-amino derivatives as potential estrone sulfatase inhibitors. We tested the inhibitory potential of these compounds using human placental microsomes, which contain a substantial amount of estrone sulfatase activity. Several compounds in the series significantly inhibited estrone sulfatase activity of the human placental microsomes when present at 10 microM. The IC50 for the estrone-3-amino compounds ranged from 8.7 to 14.6 microM. We next tested the ability of the estrone-3-amino derivatives to inhibit growth of the estrogen-dependent MCF-7 breast cancer cell line. MCF-7 cells showed substantial proliferation in the presence of 100 nM estrone sulfate in estrogen-free media, indicating that the cells were capable of converting estrone sulfate into estrone. The proliferative effect of estrone sulfate (1 microM) was significantly blocked by the estrone-3-amino derivatives at 10 microM. The magnitude of MCF-7 cell inhibition resulting from treatment with the estrone-3 amino compounds was similar to or exceeded that of Danazol, but was less than the level resulting from treatment with estrone sulfamate. Using data from all of the compounds tested, inhibition of MCF-7 cell proliferation was positively correlated with inhibition of placental estrone sulfatase activity, suggesting that the reduction in cell growth was attributable to the blockade of sulfatase activity. In support of this, there was no relationship between inhibition of estrone sulfatase activity and inhibition of cell growth when the estrogen-independent cell line MDA-MB-231 was used. Our results indicate the possible utility of estrone-3-amino derivatives for inhibition of estrone sulfatase activity. Further, our data support the concept that estrone sulfatase inhibitors may be useful as therapeutic agents for estrogen-dependent breast cancers.

Adenocarcinoma↗
PubMed1998

Differential short-term distribution of estrone and oleoyl-estrone administered in liposomes to lean and obese Zucker rats.

Thirteen-week-old female Zucker lean (Fa/Fa) and obese (fa/fa) rats were injected through a cannula inserted in the left jugular vein with 1 mL/kg of 3H-labeled oleoyl-estrone in liposomes (Merlin-2) (i.e., 670 fmol, 84 kBq). The rats were killed 10 minutes later and dissected. The presence of intact or hydrolyzed oleoyl-estrone was later determined in all samples. The pattern of distribution of estrone was quite different from that of oleoyl-estrone both in rats that were lean and in those that were obese. Estrone was better retained by white adipose tissue than oleoyl-estrone. Liver, spleen, and lungs accumulated more oleoyl-estrone and split part of it, from 4.7% (lung, obese) to 27% (liver, lean). The overall high retention of estrone by the rat tissues results in its very low circulating levels. The fast splitting of liposome-carried oleoyl-estrone by most tissues (up to more than 67% by intestine and skin of lean rats) may help explain the rise in blood free estrone. The differences between lean and obese Zucker rats are mainly quantitative in the case of estrone, the main differences being found in blood and adipose tissues. However, when we compare the data for oleoyl-estrone, the differences cannot be dismissed simply as due to differences in body size or the extent of fat deposits. A large portion of the label remained in the blood of the rats that were obese but not in those that were lean, the tissues of which took up more label. Brown adipose tissue shows a fair affinity for oleoyl-estrone in the rats that were lean but practically does not retain label in the rats that were obese, suggesting that oleoyl-estrone may have a direct effect on brown adipose tissue. The decreased uptake of oleoyl-estrone in rats that were obese shows that the mechanism regulating the turnover or disposal of this signal is altered in this type of genetic obesity.

Adipose Tissue↗
PubMed2003

Formation of estrone and estradiol from estrone sulfate by normal breast parenchymal tissue.

The study was designed to determine the process and limitations by which estrone sulfate may be a precursor of estradiol in the parenchymal cells of the normal breast. The concentration of estrone sulfate in breast nipple aspirate fluid was 1000-fold greater than that of estradiol. Concentrations of 3H-estrone sulfate in parenchymal cells were only 0.20-0.33 times that of the 1.0 nM concentration in the medium, while 3H-estrone achieved concentrations up to 24 times that in the medium at 37 degrees C. Nevertheless, estrone sulfate added to the medium was linearly converted within a 1000-fold concentration range to estrone in intact cells with a mean half-time of conversion of 628 min per 10(6) cells. Homogenized cells had a half-time of 246 min per 10(6) cells. Thus, the time for entry of estrone sulfate into cells reduced the rate by approximately 55%. In split samples, the Vmax values (+/- S.D.) for intact and homogenized cells were 12.6 +/- 1.4 and 18.3 nmol/h mg DNA, respectively (P<0.03). The corresponding Km values for intact and homogenized cells were 6.0 +/- 1.1 and 4.7 +/- 1.0 microM. Conversion of estrone sulfate to estradiol was more efficient in intact cells than in homogenates with mean half-times of 2173 and 7485 min per 10(6) cells, respectively. Conversion of estrone to estrone sulfate did not occur in these cells despite sulfonation of estrone by MCF-7 breast cancer cells under identical conditions. It is concluded that estrone sulfate can serve as a precursor for estradiol in normal breast tissue. Conversion of estrone to estradiol is a limiting step in the process.

Adult↗
PubMed1997

Estrone sulfonates as inhibitors of estrone sulfatase.

In our continuing quest to design efficient inhibitors of estrone sulfatase activity and to assess the recognition of estrone sulfate surrogates by estrone sulfatase, we synthesized and evaluated several sulfonate derivatives of 5,6,7,8-tetrahydronaphth-2-ol and estrone. 5,6,7,8-Tetrahydronaphth-2-methanesulfonate (11), and 5,6,7,8-tetrahydronaphth-2-(p-toluene)sulfonate (12) were found not to inhibit estrone sulfatase activity; estrone-3-methane-sulfonate (5), estrone-3-ethanesulfonate (6), estrone-3-butanesulfonate (7), and estrone-3-[(+)10-camphor]sulfonate (8) all weakly inhibited estrone sulfatase, and the best inhibitor, from this class of compounds, was estrone-3-(p-toluene)sulfonate (9). At 10 microM, it inhibited estrone sulfatase activity by 91%. These results emphasize some of the requirements needed for high-affinity binding to the enzyme.

Chromatography, Thin Layer↗
PubMed1981

Intestinal first-pass effects of estrone sulfate and estrone in the rat.

Mixtures of (14C)-estrone and (3H)-estrone-sulfate (10 micrograms and 13 micrograms, respectively) were instilled into the lumina of intact jejunal loops of rats. Estrone was faster absorbed into portal blood than was estrone-sulfate (72% vs. 17% in 30 min). In portal blood the chemical forms derived from estrone were: unchanged estrone (72%), estrone-glucuronide (14%), estrone-sulfate (5%) and estradiol (9%); no estriol was formed. The chemical forms of estrone sulfate were: estrone-sulfate (86%), estrone (6%), estrone-glucuronide (2%), estradiol (2%) and estradiol-sulfate (4%). These metabolites were also found in the lumen. It is concluded that the intestinal first-pass effects do not significantly influence the hormonal activities of the two estrogens.

Animals↗
PubMed1995

Estrone sulfate analogs as estrone sulfatase inhibitors.

The high serum concentration of estrone sulfate and the presence of estrone sulfatase in breast tumors constitute an important mechanism of local synthesis of estrogens in the tissue. Thus, inhibitors of estrone sulfatase may be effective in the treatment of estrogen-dependent breast cancer. In this study, we synthesized several isostructural analogs of estrone sulfate (estrone-3-methylsulfonate, estrone phosphate, 3-desoxyestradiol-3-methylenesulfonate, and 3-desoxyestrone-3-methylenesulfonate) and tested them on human placental sterylsulfatase. The results were (i) The Ki of 3-desoxyestrone-3-methylenesulfonate 12 and 3-desoxyestradiol-3-methylenesulfonate 7 are more than 100-fold higher than the Ki or KM values for estrone sulfate, (ii) As compared to estrone sulfate, the Ki value for estrone-3-methylsulfonate 2 is about 30-fold higher, while estrone phosphate 3 is bound by the sulfatase with roughly the same affinity as estrone sulfate. The results shed some light on the electronical and sterical requirements for high affinity binding to the enzyme.

Binding Sites↗
PubMed1993

Inhibition of estrone sulfatase activity by estrone-3-methylthiophosphonate: a potential therapeutic agent in breast cancer.

Many breast tumors are hormone dependent, and there is evidence that hydrolysis of estrone sulfate (E1S) to estrone, by estrone sulfatase, is an important source of the estrogen which is found in tumors. In this study, we have developed a novel pathway for the synthesis of estrone-3-methylthiophosphonate (E1-3-MTP) and examined its ability to inhibit estrone sulfatase activity in MCF-7 breast cancer cells and human placental and breast tumor preparations. In MCF-7 breast cancer cells, E1-3-MTP, 100 nM and 10 microM, inhibited estrone sulfatase activity by 52 and > 98%, respectively. The apparent Km and Vmax for E1S were 4.8 microM and 148 pmol/min/mg for placental and 16.9 microM and 38 pmol/min/mg for breast tumor preparations. Kinetic studies revealed that E1-3-MTP inhibited estrone sulfatase in a competitive manner with the Ki values for placental and tumor preparations being 14.6 and 32.8 microM, respectively. A comparison of the metabolism of [3H]E1S and [3H]E1-3-MTP by human placenta or rat liver revealed that, whereas 50-60% of [3H]E1S was converted to [3H]estrone, < 3% of [3H]E1-3-MTP was hydrolyzed. The development of an efficient inhibitor of estrone sulfatase, which is resistant to metabolism, will allow the importance of the estrone sulfatase pathway of estrogen formation in breast tumors to be assessed and such an inhibitor may have considerable potential as a therapeutic agent.

Animals↗
PubMed1984

Estrone and dehydroepiandrosterone sulfatase activities in guinea-pig uterus and liver: estrogenic effect of estrone sulfate.

Estrone and dehydroepiandrosterone (DHA) sulfatase activities were studied in the uterus and liver of female guinea-pigs (albino variety). The two activities were found in particulates, with the highest specific activity in microsomes. The effects of pH, buffers, temperature and the non-competitive inhibition of DHA sulfate on estrone sulfatase provided arguments for the existence of two distinct sulfatases. However, acrylamide gel electrophoresis of the solubilized microsome sulfatases gave a single peak for the two activities. In the uterus, the apparent Km of estrone and DHA sulfatases were 26.4 and 15.6 microM. Solubilized microsomal estrone sulfatase was inhibited by unconjugated steroids. The apparent Km of estrone sulfatase in liver was 10.7 microM. Estrone and DHA sulfatase activities were consistently lower in liver than in uterus and no DHA sulfatase activity was detected in fetal liver. In the uterus, the same sulfatase activities were found in female fetuses, castrated or mature females. Estrone sulfatase was significantly increased in the uterus of pregnant females (60-65 days gestation). Estrone sulfate was injected in vivo into mature castrated females. A significant increase in uterine weight and in uterine progesterone receptors was observed. The cytosol progesterone receptors were characterized by their Kd (1.40 nM) and by sucrose density gradient. It is concluded that the variations of estrone sulfatase activity in target tissues like the uterus may control the intracellular levels of biologically active estrogens.

Animals↗
PubMed1989

Plasma levels of estradiol, estrone, estrone sulfate and sex hormone binding globulin in patients receiving rifampicin.

Plasma estrone, estradiol, estrone sulfate, androstenedione, testosterone and sex hormone binding globulin were measured in 14 patients (3 postmenopausal women, 11 men) with tuberculosis who received rifampicin. During treatment a moderate, but significant increase in the plasma level of estradiol (mean increase 32%, P less than 0.01) and estrone (mean increase 13%, P less than 0.01) were seen. In contrast, plasma estrone sulfate was significantly reduced (mean reduction of 25%, P less than 0.05). No alteration in plasma testosterone was observed, but there was a slight (mean 15%) increase in plasma androstenedione of borderline significance (P = 0.052). In eight patients, from whom all tuberculostatic treatment except rifampicin had been withdrawn, plasma sex hormone binding globulin was found to be increased by 75% by rifampicin treatment. Further, the results obtained in this part of the study confirmed the alteration in plasma estrone sulfate to be caused by rifampicin alone without any contribution from other tuberculostatic drugs. While plasma estradiol could be increased due to elevation of sex hormone binding globulin, plasma estrone was probably increased secondary to the increase in plasma androstenedione. A reduced plasma estrone sulfate level suggests that rifampicin enhances the rate of estrone sulfate metabolism. The possibility that treatment with drugs which reduce plasma estrone sulfate might be beneficial for hormone dependent cancers is discussed.

Adult↗
PubMed1978

16-Hydroxylation of estrone-3-sulfate and estrone in the guinea pig in vivo.

[6,7-3H]Estrone-3-sulfate or [6,7-3H]-estrone of high specific activity was injected into adult female English Shorthair guinea pigs. Blood, liver, kidney, gall bladder bile, and urine were obtained and investigated for metabolites. Chromatographic procedures followed by enzymatic or solvolytic cleavage of conjugates and subsequent crystallization with appropriate carrier steroids revealed the pattern of metabolites formed. Injected estrone sulfate was partially hydrolyzed and reconjugated, resulting in the production of estrone and estradiol glucuronides. The main metabolites, however, were monosulfates of 16alpha-hydroxyestrone, 16-keto-17beta-estradiol, and estriol as well as disulfates of 16alpha-hydroxyestrone, estriol, and 16beta-hydroxyestrone. Particularly high amounts of these were found in urine. By far the main metabolites of injected estrone were glucuronides of estrone and estradiol, although the pattern of mono- and disulfated steroids was qualitatively similar to that found after estrone sulfate injection. It is concluded that the guinea pigs employed in the study hydroxylated estrogen in the 16alpha- and 16beta-configurations and that this activity was much more pronounced after injection of estrone sulfate than after estrone.

Animals↗
PubMed1983

Estriol and estrone interaction with the estrogen receptor. II. Estriol and estrone-induced inhibition of the cooperative binding of [3H]estradiol to the estrogen receptor.

Kinetic analysis of the estrogen receptor's cooperative equilibrium [3H]estradiol binding (Sasson, S., and Notides, A. C., (1982) J. Biol. Chem. 257, 11540-11545) provides a sensitive method for probing the binding of partial agonists to the estrogen receptor. We studied the effects of estriol and estrone on the positive cooperativity of [3H]estradiol binding to the partially purified, calf uterine estrogen receptor. The receptor was titrated with variable concentrations of [3H]estradiol in combination with estriol or estrone, while maintaining a constant molar ratio of the estriol or estrone to the [3H]estradiol. With either a 4-fold molar excess of estriol or a 25-fold molar excess of estrone above the [3H]estradiol concentrations, the receptor's positive cooperative [3H]estradiol binding was inhibited. The Scatchard plot showed a transition from a convex to a linear curve and a decrease in the Hill coefficient value from 1.61 +/- 0.02 (n = 7) in the absence of estriol or estrone to 1.04 +/- 0.04 (n = 4) in the presence of estriol and 0.99 +/- 0.03 (n = 4) in the presence of estrone. The inhibition of the positive cooperativity of [3H]estradiol binding by estriol or estrone was shown not to be due to isotope dilution of the specifically bound [3H]estradiol by the unlabeled estriol or estrone. These kinetic analyses demonstrate that the positively cooperative equilibrium binding of [3H]estradiol by the receptor, which is characteristic of the receptor's activation process, is eliminated by estriol and estrone and consistent with their partial agonist-antagonist activities observed in vivo.

Animals↗
PubMed1985

Conversion of estrone to estradiol and estradiol to estrone in postmenopausal women.

The conversion of estrone to estradiol and metabolism of estradiol to estrone have been measured in postmenopausal women to examine factors that influence these conversions. Transfer constants for the conversion of estrone to estradiol and estradiol to estrone were not significantly correlated with age (r = -.01 and r = .1, respectively) or subjects' percentage of ideal body weight (r = -.25 and r = -.22, respectively). There was a significant negative correlation between the transfer constants for the conversion of estradiol to estrone and plasma levels of dehydroepiandrosterone sulphate (r = -.45, P less than .05) but not plasma levels of progesterone. Transfer constants for the conversion of estrone to estradiol and metabolism of estradiol to estrone in women with breast or endometrial disease were similar to values in normal women, but metabolism of estradiol to estrone was elevated in two women with primary biliary cirrhosis.

Aged↗