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PubMed2001

Estrone, but not 17 beta-estradiol, attenuates kainate-induced seizures and toxicity in male mice.

Estrogens change the susceptibility to seizures in humans and experimental animals. In this study, the effect of estrone and 17 beta-estradiol on kainate-induced seizures and neurotoxicity was investigated in male mice. Pre-treatment with estrone (250-1000 micrograms/kg) at 24 and 2 hours before kainate (40 mg/kg) administration significantly decreased both the percentage of animals with clonic seizures and their mortality (the latter at a dose of 1000 micrograms/kg only). On the other hand, 17 beta-estradiol (10-500 micrograms/kg) had no effect on seizures, and its dose of 10 micrograms/kg increased mortality. When given alone at a dose of 1 mg/kg, tamoxifen, an antagonist at estrogene receptors, did not affect the kainate-induced seizures, but prevented the anticonvulsant effect of estrone. A histological analysis showed that 73% of mice injected with vehiculum and kainate incurred hippocampal damage. Estrone (2000 micrograms/kg) decreased the percentage of animals with hippocampal neuronal loss down to 43%, and that effect was not antagonized by tamoxifen. Pretreatment of mice with 17 beta-estradiol had no effect on the kainate-induced neuronal loss. Additionally, we found that kainate injected i.p. had a profound effect on the immune system of mice, as reflected by a decrease in the thymus weight and an increased metabolic activity of splenocytes. The anticonvulsive dose of estrone (1000 micrograms/kg) did not change the immunoreactivity of either control or kainate-treated mice. In conclusion, the obtained data indicate that estrone, but not 17 beta-estradiol, attenuates the kainate-induced seizures, mortality and excitotoxicity in male mice. Moreover, it is suggested that the suppressive effect of estrone on clonic seizures involves intracellular receptors, whereas its antineurotoxic activity seems to depend on a non-genomic mechanism.

Animals↗

PubMed1983

Monitoring ovulation and implantation in the lion-tailed macaque (Macaca silenus) through urinary estrone conjugate evaluations.

Urine samples were collected daily during ten nonfertile and four fertile ovarian cycles of four adult female lion-tailed macaques (Macaca silenus). Urine was analyzed for concentrations of total immunoreactive estrogen (Et), estrone conjugates, and bioactive luteinizing hormones (LH). The estrone conjugates of selected samples were separated by high-performance liquid chromatography (HPLC) to evaluate the relative proportions of estrone glucuronide (E1 G) to estrone sulfate (E1 S) contributing to the sum total of the conjugate measured in the samples. The estrone conjugate profile was found to accurately reflect the preovulatory estrogen peak in both nonfertile and fertile cycles as well as the early pregnancy increase which was found to be statistically significant on Day + 14 postovulation (P = 0.003). Estrone conjugate levels rose in the early follicular phase from 126.00 +/- 24.07 (SEM) ng/mg creatinine to a preovulatory peak of 471.90 +/- 62.95 ng/mg creatinine. Fertile cycles exhibited a postovulatory climb to a peak of 515.00 +/- 38.00 ng/mg creatinine on Day + 19, in contrast to the secondary rise observed in nonfertile cycles that peaked at 148.11 +/- 13.80 ng/mg creatinine on Day + 10. Bioactive LH evaluations confirmed ovulation and, in the fertile cycles, reflected the subsequent elevation of chorionic gonadotropin on Day + 18. The estrone conjugate profile of fertile cycles and early pregnancy compared favorably to the Et profile: both showed the same time course and increases in estrogen excretion.

Animals↗

PubMed2004

Involvement of estrone-3-sulfate transporters in proliferation of hormone-dependent breast cancer cells.

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 microM 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-17beta-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.

Breast Neoplasms↗

PubMed1987

Tissue-specific concentration changes of estrone and estradiol during spontaneous and ACTH-induced parturition in sheep.

Changes in estrogen production are considered important in the sequence of events leading to parturition. We sought tissue-specific changes in the concentration of unconjugated estrone (E1) and estradiol (E2) in intrauterine fetal (amnion, chorion) and maternal (endometrium, myometrium) tissues during normal pregnancy, labour, and ACTH-induced labour in sheep. The mean concentrations of E1 and E2 in the fetal membranes were higher than in endometrium and myometrium. In amnion there were no consistent changes in estrone concentrations with gestation, although estradiol concentrations increased between day 130 and term. In the endometrium there were increases in both estrone and estradiol between day 100 and term, whereas in the myometrium increases in the concentrations of E1 and E2 occurred between days 130-135 and term. Animals showing a labourlike pattern of uterine contractions after intrafetal ACTH administration did not show significant differences in estrone or estradiol concentrations in amnion, chorion, or endometrium compared with saline-infused controls. However, there was a progressive increase in the concentration of estrone and estradiol in the myometrium during ACTH-induced labour. We conclude that changes in the concentrations of estrone and estradiol in intrauterine tissues vary between the tissues studied and the two estrogens. In general, estrogen concentrations increased towards term, but this trend was more marked in the maternal than fetal tissues. The changes in estrone concentrations in myometrium, but not in the other tissues, were replicated during ACTH-induced labour. Our results would be compatible with the suggestion that tissue-specific changes in estrogen concentrations may contribute to the local intrauterine steroid milieu during pregnancy and at term.

Adrenocorticotropic Hormone↗

PubMed1977

[In vitro metabolism of (6,7-H3)estrone and of (6,7-H3) estradiol by the liver in pregnant guinea pigs].

Slices of pregnant guinea pig liver were incubated with (6,7-3H)estrone and with (6,7-3H)estradiol. Free, glucuro- and sulfo-conjugated fractions were isolated by specific extraction and hydrolysis. The radioactivity distribution in these 3 fractions demonstrated a predominance of conjugated compounds (95% of isolated estrogens) with slightly more glucuro-conjugated than sulfo-conjugated compounds. After isolating estrogens by TLC, we were able to determine estrone and estradiol in these 3 fractions from incubations with 3H-estrone or with 3H-estradiol by means of specific activity recrystallisation. Estriol was determined in glucuro-and sulfo-conjugated fractions after incubation with 3H-estrone as well as in sulfo-conjugated fraction after incubation with 3H-estradiol. Glucuro- or sulfo-conjugated estrone was the predominant estrogen after incubation with 3H-estrone just as after incubation with 3H-estradiol. This led us to conclude to an important 17beta-hydroxysteroid-dehydrogenase activity. The 16alpha-hydroxylastic-activity is weaker since estriol represented only 1,43 % of estrogens isolated after incubation with 3H-estrone and 0.82% after incubation with 3H-estradiol.

17-Hydroxysteroid Dehydrogenases↗

PubMed2004

Oleoyl-estrone metabolic effects in relation with caloric restriction in inbred Beta rats with spontaneous obesity and type 2 diabetes.

Spontaneously hypertriacylglycerolemic obese and diabetic inbred IIM Beta rats were treated with oleoylestrone for 10 days. Pair-feeding was performed to determine some oleoyl-estrone effects dependent on the caloric restriction it promotes. Twenty-five 200 day-old Beta males receiving a daily gavage of 0.2 ml sunflower oil were divided into the following groups: 1) daily dose of 10 nmol/g oleoyl-estrone; 2) pair-fed; 3) control. The variables measured were: whole body protein, water and lipid; retroperitoneal and epididymal fat depot weights; plasma urea, glucose, insulin, triacylglycerols and cholesterol. Biomass and food intake were assessed daily. Oleoyl-estrone and pair-fed groups expressed similar variations in body composition and significant body weight losses due to reduction in food intake. Oleoyl-estrone and pair-fed treatments significantly reduced retroperitoneal fat depot weights, but not epididymal ones. In oleoyl-estrone and pair-fed groups hyperglycemia decreased and insulinemia lowered significantly. Plasma normal total cholesterolemia and hypertriacylglycerolemia values typical of Beta rats decreased strongly compared to controls, though attaining significantly different values between oleoyl-estrone and pair-fed groups. Plasma total cholesterol appeared as more sensitive to caloric restriction than triacylglycerols through a specific oleoyl-estrone-mediated effect.

Animals↗

PubMed1987

[Biological responses, ultrastructural changes and metabolism of estrone sulfate in line cells of human breast cancer: MCF-7].

The biological responses, the metabolism and the ultrastructural modifications provoked by estrone sulfate in the MCF-7 mammary cancer cell line are studied. The data indicate: 1) A fraction of estrone sulfate is hydrolyzed and the freed hormone is sufficient to elicit a biological response (progesterone receptor). 2) Using [3H]estrone sulfate, 24 h after culture, it is observed that the great part of the radioactive material in the cells is in the form of unconjugated estrogens. 3) The main transformation product of [3H]estrone sulfate is estradiol. This is found particularly in the nucleus. 4) Tamoxifen inhibits very significantly the conversion of estrone sulfate into estradiol. 5) Electronmicroscopic observations indicate that the estrone sulfate provokes an important development in the secretory system. In conclusion, it is suggested that the estrone sulfate can play an important role in the response to estrogens in human mammary cancer.

Breast Neoplasms↗

PubMed1982

Estrone receptor formation during the processing of estradiol-receptor complex in MCF-7 cells.

Human breast cancer cells (MCF-7, maintained in long-term culture) contain separate estrogen receptors specific for either 17 beta-estradiol or estrone. Utilizing optimum conditions for the protamine sulfate assay, it has been possible to demonstrate both receptors in the 0.6 M KCl extract of nuclei and in the cytosol. Similarly, in the exchange assay, high-affinity low-capacity binding sites for 17 beta-estradiol and estrone have been found in the salt-extracted nuclear residue. Dissociation constants and binding capacities were determined for either receptor in the absence of the other [e.g., estrone receptor (E1R) in the cytosol or nuclear residue from 17 beta-estradiol-stimulated cells] or, when both receptors were present, a saturating amount of the other estrogen (unlabeled) was added to the assay mixture (e.g., the salt-extractable nuclear receptors). Specificity was demonstrated by the inability of estrone to compete with 17 beta-[2,4,6,7-3H]estradiol for the 17 beta-estradiol receptor (E2R) at molar excesses less than 10-fold. Likewise, there was no inhibition of [6,7-3H]estrone binding to its receptor by molar excesses of 17 beta-estradiol below 100-fold. Other steroid hormones were very weak competitors of [6,7-3H]estrone, even at 1000-fold molar excesses. The quantitative relationships of these two estrogen receptors were shown to fluctuate in the various cellular compartments following incubation (37 degrees) of MCF-7 cells with 10(-8) M 17 beta-estradiol. This level of 17 beta-estradiol elicited the translocation of all detectable cytosolic E2R to the nucleus, where, after an incubation of 1 hr, the salt-resistant 17 beta-estradiol disappeared and 40% of the extractable 17 beta-estradiol-binding capacity was lost (processed). Simultaneously, the E1R which remained in the nuclear residue appeared in the nuclear extract, and ultimately this receptor accumulated in the cytosol. The estrone-binding capacity (0.78 pmol/mg DNA) which appeared following the processing of E2R nearly equalled the loss of 17 beta-estradiol binding sites per cell (0.85 pmol/mg DNA). Concentrations of 17 beta-estradiol which elicited the greatest processing of E2R in these incubations brought about the appearance of maximum levels of E1R in MCF-7 cells. Considering these results in the light of data previously reported from this laboratory concerning the metabolic and ligand fate of 17 beta-[3H]estradiol in MCF-7 cells, processing would appear to involve the formation of E1R in the salt-resistant nuclear compartment followed by the accumulation of E1R in the cytosol.

Binding, Competitive↗

PubMed1998

Different biochemical properties of nuclear and microsomal estrone-3-sulfatases: evidence for the presence of a nuclear isozyme.

In female rats, total estrone-3-sulfatase activity per liver in the nuclear fraction is comparable to the total activity per liver in the microsomal fraction. The combined estrone-3-sulfatase activity in the other fractions (lysosomal, mitochondrial, and cytosolic fractions) is negligible and only accounts for < 5% of the total nuclear or microsomal sulfatase activity. Nuclear and microsomal estrone-3-sulfatases have different pH optima (pH 8.0 and 7.2, respectively). The apparent Km values for the nuclear and microsomal estrone-3-sulfatases are 2.5 and 10.1 microM, respectively, suggesting that the nuclear sulfatase has a considerably higher affinity for estrone-3-sulfate than the microsomal sulfatase. Moreover, the nuclear estrone-3-sulfatase is more sensitive to inhibition by several steroids than the microsomal sulfatase. The results suggest that estrone-3-sulfatase in the nuclear fraction is a different isozyme than that in the microsomal fraction.

Animals↗

PubMed1995

Secretion of unconjugated estrone during pregnancy and around parturition in goats.

The secretion of unconjugated estrone and its production site in pregnant goats were investigated in vivo. The mean estrone concentration (n = 15) in the peripheral plasma increased gradually, being 83 pg/ml on Day 40 and 483 pg/ml on Day 140 after mating. The estrone concentration increased rapidly after Day 2 before partum, reaching a peak at parturition (2370 pg/ml), and falling to 171 pg/ml at Day 1 post partum. The concentrations of estrone from the umbilical vein and umbilical artery did not differ from that found in the maternal jugular vein, suggesting that the fetus does not take part in estrogen production. The estrone concentration from the uterine vein after the fetus was removed was higher than the concentrations found in the maternal jugular vein and umbilical artery. In the placental tissue, a high concentration of estrone (18157 pg per gram of wet tissue) was detected. These findings suggest that the main production site of unconjugated estrone is the placenta.

Journal Article↗

PubMed2001

Immunohistologic localization of estrone sulfatase in uterine endometrium and adenomyosis.

OBJECTIVE: To clarify histologic localization of estrone sulfatase in normal uterine endometrium and adenomyotic tissue and to confirm that estrone sulfatase is one of the enzymes that supplies estrogen to adenomyotic tissue. METHODS: Specimens from 21 patients who had undergone hysterectomy were obtained from uteri with histopathologically proven adenomyosis. Specimens from 28 patients who had undergone hysterectomy for a disease of the uterine cervix were used as control specimens of normal uterine endometrium. Cases of hormone-dependent disease, such as leiomyoma, adenomyosis, and endometrial neoplasm, were excluded from cases of normal endometrium. The myometrium in patients with adenomyosis was examined. These tissues were examined by immunohistochemistry using anti-estrone sulfatase monoclonal antibodies. Power analysis was performed. With alpha = 0.05, 1 - beta = 0.8, P1= 25%, and P2 = 75%, 14 specimens from each group were sufficient to detect significant differences among them. The Fisher exact test, sign test, and McNemar test were used for statistical analysis. RESULTS: In normal endometrial tissue, immunostaining for estrone sulfatase was observed only on the glandular epithelial cells of the basilar layer of the endometrium. However, all functional layers of the endometria were negative for staining for estrone sulfatase. In adenomyotic tissue, glandular epithelial cells showed immunostaining for estrone sulfatase. Rates of immunostaining in adenomyotic tissue were higher than those in the basilar layer of normal uterine endometrium (76% and 43%, respectively, P =.02). The myometrium was not stained. CONCLUSION: Estrone sulfatase may be one of the enzymes supplying estrogen for growth of adenomyosis.

Adult↗

PubMed2000

Oleoyl-estrone induces the massive loss of body weight in Zucker fa/fa rats fed a high-energy hyperlipidic diet.

To test whether oleoyl-estrone plus a hyperlipidic diet affects body weight in Zucker fa/fa rats, 13-week-old male Zucker obese (fa/fa) rats initially weighing 440-470 g were used. They were fed for 15 days with a powdered hyperlipidic diet (16.97 MJ/kg metabolizable energy) in which 46.6% was lipid-derived and 16.1% was protein-derived energy and containing 1.23 +/- 0.39 µmol/kg of fatty-acyl esters of estrone. This diet was supplemented with added oleoyl-estrone to produce a diet with 33.3 µmol/kg of fatty-acyl estrone. Oral administration of oleoyl-estrone in a hyperlipidic diet (at a mean dose of 0.5 µmol. kg(-1).d(-1)) resulted in significant losses of fat, energy and, ultimately, weight. Treatment induced the maintenance of energy expenditure combined with lower food intake, creating an energy gap that was filled with internal fat stores while preserving body protein, in contrast with the marked growth of controls fed the hyperlipidic diet. Treatment of genetically obese rats with a hyperlipidic diet containing additional oleoyl-estrone resulted in the loss of fat reserves with scant modification of other metabolic parameters, except for lower plasma glucose and insulin levels. The results agree with the postulated role of oleoyl-estrone as a ponderostat signal.

Journal Article↗

PubMed1986

[Demonstration of a cytosolic inhibitory of membrane estrone sulfatase activity in guinea pig liver].

Estrone sulfatase is a membrane-bound enzyme hydrolysing estrone sulfate. In normal and pathological tissues, estrone sulfatase is required for the conversion of estrone sulfate into physiologically active estrogens. In the hepatic cytosol of Guinea-pig, we have demonstrated the existence of a soluble inhibitor of uterine and hepatic microsomal estrone sulfatase. This inhibitor has approximatively a molecular weight of 7,600 and acts as a non-competitive inhibitor of estrone sulfatase. It seems to be a soluble intra-cellular effector of membrane-bound estrone sulfatase.

Animals↗

PubMed1998

Scavestrogen sulfamates: correlation between estrone sulfatase inhibiting and antioxidant effects.

In the present study estrone sulfatase (steryl-sulfatase; EC 3.1.6.2) and phenylsulfatase (arylsulfatase B; EC 3.1.6.1) inhibiting as well as antioxidant effects exerted by ring B,C unsaturated sulfamates of estrone (J 1025), 17 beta-estradiol (J 1054, J 1059, J 1067), and 17 alpha-estradiol (J 1051, J 1064, J 1065) were examined as compared with their parent compounds, J 994, J 995, and J 1050, using six different in vitro models: (i) estrone sulfatase activity in human placental microsomes, (ii) phenylsulfatase activity isolated from Helix pomatia, (iii) Fenton reaction driven lipid peroxidation in rat synaptosomes, (iv) Fe(II)-chelating activities, (v) formation of superoxide anion radicals, and (vi) total antioxidative activities. Ring B,C unsaturated estrogen (so-called scavestrogen) sulfamates were found to act as potent inhibitors of the following enzyme activities and generated radicals: estrone sulfatase, phenylsulfatase, lipid peroxyl, and superoxide anion. In addition, scavestrogen sulfamates were able to influence the iron redox chemistry and total antioxidative activities. These findings indicate that relatively minor modifications in the chemical structure of classical steroid sulfamates can preserve or enhance their estrone sulfatase inhibiting properties and, simultaneously, amplify their antioxidant capacity to a great extent. Taken together, our data suggest that scavestrogen sulfamates such as J 1025, J 1051, or J 1054 (17 beta-dihydroequilenin sulfamate) may serve as a very promising basis for the development of steroid-derived estrone sulfate-sulfatase inhibitors characterized by promising estrone sulfatase inhibiting activities in combination with a "good" antioxidant potency.

Adult↗

PubMed2001

Effect of 24-h food deprivation on lipoprotein composition and oleoyl-estrone content of lean and obese Zucker rats.

BACKGROUND: Food deprivation induces the mobilization of fat reserves and, consequently, the transport of lipids in plasma. Zucker obese rats are grossly hyperlipidemic and do not use lipids as an efficient energy substrate. They also have lower circulating levels of acyl-estrone than expected because of their large fat stores. AIM OF THE STUDY: To measure the effect of 24 h food deprivation on hyperlipidemia and acyl-estrone distribution in plasma in Zucker obese rats. METHODS: The plasma lipoprotein distribution and composition of Zucker lean (Fa/?) and obese (fa/fa) rats was determined after 24 hours of food deprivation. Lipid classes: phospholipid, free and esterified cholesterol and triacylglycerols, and protein and total (mainly acyl-) estrone were also measured in total plasma and lipoprotein fractions. RESULTS: Food-deprived rats showed lower triacylglycerol levels than fed rats, but obese rats maintained high lipid levels, mainly in the VLDL fraction. The ratio of total plasma free-to-esterified cholesterol was lower in fed lean rats (0.29) than in the obese (0.61); the situation improved slightly after 24-h starvation, since the corresponding ratios were 0.30 and 0.41. Acyl estrone levels changed little with 24-h food deprivation. The chylomicra + VLDL total estrone compartment was essentially unchanged in lean and obese fed and starved groups, but the HDL pool decreased with food deprivation in the obese. CONCLUSION: Short-term starvation helped to enhance the differences between lean and obese Zucker rats in the handling of lipoprotein lipids, the latter showing a marked impairment in their ability to dispose of circulating lipids. The different pace of plasma lipid utilization may compound the problems of cholesterol transfer, partly explaining the dyslipemia that characterizes this animal model of obesity. The differences in acyl-estrone distribution also indicate that fat mass is preserved more effectively in obese rats even after food deprivation.

Adipose Tissue↗

PubMed2001

Dietary oleoyl-estrone delays the growth rate of young rats.

BACKGROUND: Oleoyl-estrone administration induces the rapid loss of fat preserving body protein. AIM OF THE STUDY: We intended to check whether the fat-shedding effect of oleoyl-estrone arrests growth in young rats, limiting the buildup of protein and fat. METHODS: Oleoyl-estrone diluted in a powdered hyperlipidic diet (33 mumol/kg) was given for 30 days to 30-day old Zucker lean (Fa/?) rats. Their body weight and food consumption were followed daily; on day 30 of treatment (60-day old rats), whole body composition (lipid, protein) was determined, and plasma energy parameters and leptin were measured. RESULTS: Oleoyl-estrone-treated rats grew more slowly than controls fed the hyperlipidic diet alone, and on day 60 their lipid content was about half that of controls. Protein content per kg was identical in both groups, but treated rats tended to accumulate less nitrogen and energy because of their smaller size. No changes in plasma glucose, urea, triacylglycerols or total cholesterol were observed, but oleoyl-estrone-treated rats showed lower circulating leptin than controls. CONCLUSION: Despite limiting the accumulation of lipids, oleoyl-estrone slowed, but did not arrest growth of young rats, nor elicit a loss of fat or protein.

Animals↗

PubMed1983

Gastrointestinal absorption of estrone sulfate in germfree and conventional rats.

Steroids are extensively excreted in the bile of rats. There was no significant difference in biliary excretion of steroid following administration of [3H]-estrone sulfate into the proximal small intestine (PSI) of conventional (CVL; 17.8 +/- 62%; mean +/- SD) or germfree (GF; 28.2 +/- 5.3) rats. A similar finding resulted from administration into the distal small intestine (DSI)-CVL, 22.3 +/- 11.8%; GF, 11.4 +/- 3.7%. However, when the drug was given into the caecum, excretion in the bile of CVL rats after 5 h was 59.1% whereas in GF rats it was only 1.7%. When estrone was injected into the PSI and DSI of CVL and GF rats, absorption (as judged by excretion in bile) was more rapid than that seen with estrone sulfate. Five hours after injection into the PSI, biliary excretion was, in CVL 88.2% and in GF 81.7% and after injection into the DSI excretion was, in CVL 84.7% and in GF 83.6%. Absorption of estrone from the caeca of GF rats was apparently reduced (49.0% and 25.3% excreted in the bile of CVL and GF rats respectively). There was no significant difference in bile flow rate between CVL and GF rats. These results give unequivocal evidence of intact absorption of estrone sulfate from the small intestine of the rat. The rate of absorption is however very much reduced compared to the non-sulphated steroid. Estrone sulfate is not absorbed intact in the caecum but is hydrolysed by the gut microflora prior to absorption.

Animals↗

PubMed1988

Effect of tamoxifen and tamoxifen derivatives on the conversion of estrone-sulfate to estradiol in the R-27 cells, a tamoxifen-resistant line derived from MCF-7 human breast cancer cells.

R-27 cells, a tamoxifen-resistant clone of MCF-7 mammary cancer cells, were used to study the effect of tamoxifen and its derivatives (4-hydroxytamoxifen, N-desmethyltamoxifen and cis-tamoxifen) on the conversion of estrone sulfate to estradiol. The present data indicate that (1) tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen and cis-tamoxifen inhibit the uptake of the radioactivity after incubation of these triphenylethylene derivatives with [3H]-estrone sulfate; (2) there is a significant decrease of the conversion of estrone sulfate to estradiol by these antiestrogens; (3) the concentrations of estradiol (cytosol + 0.6 M KCl nuclear extract) which are 293 +/- 50 pg/mg DNA in the control studies (estrone sulfate alone), diminish to 26 +/- 5 pg/mg DNA after addition of tamoxifen, to 9 +/- 2 with 4-hydroxytamoxifen, to 24 +/- 7 with N-desmethyltamoxifen and to 32 +/- 6 with cis-tamoxifen. It is concluded that estrone sulfate can play an important role in the biological responses to estrogens in this breast cancer cell line and tamoxifen and its derivatives block the conversion of estrone sulfate to estradiol. The decrease in concentration of estradiol could be explained by the presence of the estrogen receptor system but other ways of the action of antiestrogens remain to be explored.

Breast Neoplasms↗