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PubMed1995

Aromatase inhibitor development for treatment of breast cancer.

Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17 beta-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue. To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hr urine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Aromatase Inhibitors↗
PubMed1990

A serum-free system for culturing human placental trophoblasts.

We have compared hormone production by early gestation and term human placental trophoblasts cultured in Ham's F10 medium containing 10% fetal bovine serum with that by cells cultured in serum-free HB102 medium. Mean daily production of progesterone on Days 3 to 7 was approximately 25% less by both early gestation and term cells cultured in HB102 as compared to Ham's F10, but production was maintained at a stable level for at least 7 d longer than the cells in Ham's. Estradiol production from 10(-6) M dehydroepiandrosterone by both early gestation and term cells was comparable in both media. Human placental lactogen production on Days 3 to 7 was 40% less by cells cultured in HB102. Human chorionic gonadotropin (hCG) output by early gestation cells was also 50% less in HB102 but term cells in HB102 produced twice as much hCG as those in Ham's F10. 3B-Hydroxysteroid dehydrogenase (3BHSD) activity in early gestation and term cells and 11B-hydroxysteroid dehydrogenase (11BHSD) activity of early gestation cultures was comparable in the two media. 11BHSD activity was decreased in the term cultures, and this decrease was more marked in Ham's than in HB102. Sulfatase and aromatase activities in the early gestation cultures were comparable in both media; sulfatase activity was comparable and aromatase activity only 20% less in the term cells cultured in HB102. These results indicate that serum-free HB102 supports differentiated function of human trophoblast cells and is useful for studies of placental activity for as long as 14 d in culture.

Aromatase↗
PubMedDate not supplied

Cell features in pancreas of prediabetic and diabetic rabbits after Wirsung duct ligation. Histochemical and histoenzymatic studies.

Kinetic studies of the histochemical and histoenzymatic behavior of rabbit pancreatic parenchymas were performed 5, 30 and 90 days after Wirsung duct ligation. In control pancreas, some enzyme activities (EA) were more prominent in Langerhans islets [glucose-6-phosphatase, glucose-6-phosphate dehydrogenase (DH), isocitrate DH, glycerol-3-phosphate DH, NADPH DH], others were strongly marked in acini and ducts (alkaline phosphatase, beta-glucuronidase, acid esterase aryl-sulfatase). Histochemical and enzyme abnormalities observed in experimental rabbits reflect the post-ligation degenerative and reactive processes in both exocrine and endocrine pancreas: (1) the decrease in Krebs cycle and pentose pathway linked EA and the increased lysosomal and acid phosphatase EA reflect early (day 5) degeneration and necrosis of islets and acini (day 30); (2) proliferative processes in developed ductal epithelia are shown by an increase in both glycolytic and lysosomal EA (days 30 and 90); (3) connective tissue neogenesis and interstitial fibrosis occurred as shown by activated beta-glucuronidase, aryl-sulfatase, alkaline phosphatase and increased ribonucleoproteins and glycoaminoglycans contents (day 30); (4) on day 90, the neoformed cell clusters presenting glucose-6-phosphatase positivity (B-cell marker) are seen in the pancreas remnant. At the same time, blood insulin level increases correlated with a decrease of hyperglycemia.

Animals↗
PubMed1989

Formation of tyrosine O-sulfate by mitochondria and chloroplasts of Euglena.

Mitochondria that have been purified from cells of light-grown wild-type Euglena gracilis Klebs var. bacillaris Cori or dark-grown mutant W10BSmL and incubated with 35SO4(2-) and ATP accumulate a labeled compound in the surrounding medium. This compound is also labeled when mitochondria are incubated with [14C]tyrosine and nonradioactive sulfate under the same conditions. This compound shows exact coelectrophoresis with synthetic tyrosine O-sulfate at pH 2.0, 5.8, and 8.0, and yields sulfate and tyrosine on acid hydrolysis. Treatment with aryl sulfatase from Aerobacter aerogenes yields sulfate and tyrosine but no tyrosine methyl ester; no hydrolysis of tyrosine methyl ester to tyrosine is observed under identical conditions, ruling out methyl esterase activity in the aryl sulfatase preparation. Thus the compound is identified as tyrosine O-sulfate. No tyrosine O-sulfate is found outside purified developing chloroplasts of Euglena incubated with 35SO4(2-) and ATP, but both chloroplasts and mitochondria accumulate labeled tyrosine-O-sulfate externally when incubated with adenosine 3'-phosphate 5'-phospho[35S]-sulfate (PAP35S). Since tyrosine does not need to be added, it must be provided from endogenous sources. Labeled tyrosine O-sulfate is found in the free pools of light-grown Euglena cells grown on 35SO4(2-) or in dark-grown cells incubated with 35SO4(2-) in light, but none is found in the medium after cell growth. No labeled tyrosine O-sulfate is found in Euglena proteins (including those in extracellular mucus) after growth or incubation of cells with 35SO4(2-) or after incubation of organelles with 35SO4(2-) and ATP or PAP35S, ruling out sulfation of the tyrosine in protein or incorporation of free-pool tyrosine O-sulfate into protein. The system forming tyrosine O-sulfate is membrane-bound and may be involved in transporting tyrosine out of the organelles.

Adenosine Triphosphate↗
PubMed1987

Fibroblast growth factors are present in the extracellular matrix produced by endothelial cells in vitro: implications for a role of heparinase-like enzymes in the neovascular response.

Salt extracts of the extracellular matrix (ECM) that is produced by vascular and capillary endothelial cells contain mitogens that are indistinguishable from basic and acidic fibroblast growth factors (FGFs). The biological activity found in these extracts is retained by heparin-Sepharose affinity columns and elutes with salt concentrations similar to those required to elute FGFs (i.e. 1.1 - 2M NaCl). Antisera raised against synthetic fragments of basic and acidic FGF crossreact with the ECM-derived mitogens. Radioiodinated basic FGF binds to the ECM formed by both vascular and capillary endothelial cells, a result that is consistent with the observation that FGF-like mitogens are found on the ECM. The binding of FGF to the ECM is negligible when the ECM has been pretreated with heparinase or heparitinase suggesting that the mitogen is interacting with a heparin-like glycosaminoglycan in the ECM. The digestion of the ECM with several grades of hyaluronidase, chondroitinase or chondro-4-sulfatase or chondro-6-sulfatase has little or no effect on 125I-FGF binding to the ECM. In view of the fact that many, if not all cells, produce heparan sulfates and that these glycosaminoglycans are associated with the external surface of the cell and the ECM, a model is proposed suggesting that the neovascular response induced by tumours and some normal tissues may be mediated at least in part, by the initial release of heparinase-like enzymes rather than angiogenic factors (FGFs) per se. The release of these enzymes would effectively mobilize a secondary local release of FGF from the ECM which then induces a proliferative response.

Animals↗
PubMed1990

Enzymatic sulfation of gastrin in rat gastric mucosa.

An enzyme which catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to gastrin (G17) was identified in rat gastric mucosal cells. The enzyme activity was detected in the 105,000xg supernatant fraction. Formation of gastrin sulfate was shown by using 125I-gastrin and non-radioactive PAPS. The product was sensitive to acid hydrolysis, arylsulfatase treatment and removed by gastrin antibody, but not changed by treatments with chondro-4-sulfatase and chondro-6-sulfatase. The product had a molecular weight of 2050 daltons, close to the molecular weight of G17 sulfate, and, therefore, indicating the sulfated product is not APS derived from the degradation of PAPS. The enzyme activity showed a Km value of 5 microM for PAPS and a pH optimum of 6.0. The activity was not detected in the liver preparation.

Adenine Nucleotides↗
PubMed1984

Lysosomal enzyme release in hypothermically perfused dog kidneys.

This study investigated lysosomal disruption during hypothermic perfusion preservation of kidneys and its possible relationship to viability. The percentage of free and bound enzyme activity was analyzed for three lysosomal enzymes in homogenates made from perfused canine kidney cortex tissue, including beta-glucuronidase, cathepsin-D, and aryl sulfatase. All three enzymes displayed characteristic increases in free enzyme activity (47-68%) throughout 5 days of perfusion preservation. The increased activity obtained at 5 days of preservation was found to indicate "severe" tissue damage, as shown by a similar increase obtained in renal cortex tissue exposed to warm ischemia (37 degrees C) for 4 hr or longer. Aryl sulfatase was found to be the most sensitive indicator of severe damage. Pretreatment of kidney donors with methylprednisolone, a lysosomal stabilizer, was also studied in kidneys exposed to 5 days of perfusion. Pretreatment was found to reduce the percentage of free lysosomal enzyme activity following 5 days (nonviable) of perfusion to those levels normally obtained following 3-day (viable) perfusion. This indicates that methylprednisolone may be useful in modulating the severe disruption of lysosomes induced by long-term preservation. It is concluded that extensive disruption of lysosomes occurs during hypothermic perfusion preservation and may represent one cause for loss of organ viability.

Animals↗
PubMed1989

Importance of estrogen sulfates in breast cancer.

Estrogen sulfates are quantitatively the most important form of circulating estrogens during the menstrual cycle and in the post-menopausal period. Huge quantities of estrone sulfate and estradiol sulfate are found in the breast tissues of patients with mammary carcinoma. It has been demonstrated that different estrogen-3-sulfates (estrone-3-sulfate, estradiol-3-sulfate, estriol-3-sulfate) can provoke important biological responses in different mammary cancer cell lines: there is a significant increase in progesterone receptor. On the other hand, no significant effect was observed with estrogen-17-sulfates. The reason for the biological response of estrogen-3-sulfates is that these sulfates are hydrolyzed, and no sulfatase activity for C17-sulfates is present in these cell lines. [3H]Estrone sulfate is converted in a very high percentage to estradiol (E2) in different hormone-dependent mammary cancer cell lines (MCF-7, R-27, T-47D), but very little or no conversion was found in the hormone-independent mammary cancer cell lines (MDA-MB-231, MDA-MB-436). Different anti-estrogens (tamoxifen and derivatives) and another potent anti-estrogen: ICI 164,384, decrease the concentration of estradiol very significantly after incubation of estrone sulfate with the different hormone-dependent mammary cancer cell lines. No significant effect was observed for the uptake and conversion of estrone sulfate in the hormone-independent mammary cancer cell lines. Progesterone provokes an important decrease in the uptake and in estradiol levels after incubation of [3H]estrone sulfate with the MCF-7 cells. It is concluded that in breast cancer: (1) Estrogen sulfates can play an important role in the biological response of estrogens; (2) Anti-estrogens and progesterone significantly decrease the uptake and estradiol levels in hormone-dependent mammary cancer cell lines; (3) The control of the sulfatase and 17 beta-hydroxysteroid dehydrogenase activities, which are key steps in the formation of estradiol in the breast, can open new possibilities in the treatment of hormone-dependent mammary cancer.

Breast Neoplasms↗
PubMed1980

The galactose-specific recognition system of mammalian liver: the route of ligand internalization in rat hepatocytes.

We have used two electron microscopic tracers, asialoorosomucoid covalently coupled to horseradish peroxidase (ASOR-HRP) and lactosaminated ferritin (Lac-Fer), to investigate the internalization of proteins bound by the asialoprotein receptor of rat hepatocytes. Both ligands are cleared rapidly from the circulation of rats, are retarded in their clearance by an excess of ASOR and accumulate principally in the liver. Morphological examination of the livers of rats after injection of the probes confirmed that the hepatocyte is the principal liver cell involved in the clearance of galactose-terminating proteins. Internalization occurred via coated pits and coated vesicles of 1000 A diameter. At 30 sec to 2 min the tracers began to accumulate in a complex arrangement of larger smooth-surfaced vesicles and tubular structures at the sinusoidal periphery of the cell. Fluid phase pinocytosis did not appear to account for any of the uptake into larger vesicles. The particulate tracer, Lac-Fer, was closely apposed to the membrane of coated pits and vesicles, but was found scattered throughout the lumen of the larger vesicles, possibly indicating dissociation of the ligand from its receptor. Although occasional lysosomes were detected cytochemically in the cell periphery, vesicles containing Lac-Fer showed no demonstrable aryl sulfatase activity. At 5 min, the tracers began to appear in Golgi-lysosome regions of the hepatocyte and were present in small vesicles of <2000 A in diameter, larger irregular vesicles and tubules. Serial sectioning indicated that tubular structures in Golgi-lysosome regions were often interconnected to the larger vesicles, but that tubules in the peripheral cytoplasm were only occasionally connected to larger structures. Some of the Lar-Fer-containing vesicles in Golgi-lysosome areas at 15 min after injection were found to contain aryl sulfatase reaction product, indicating fusion with lysosomes.

Animals↗
PubMed1985

Methods for measuring mutagenicity in urine of rats dosed with [14C]di(2-ethylhexyl)phthalate.

Di(2-ethylhexyl)phthalate (DEHP) is extensively used as a plasticizer for vinyl plastic articles. It has been found to be positive in an NCI rodent bioassay but has generally given negative results in in vitro genotoxicity tests. We therefore decided to test the urine of rats fed [14C]DEHP for mutagenic activity in the Ames Salmonella test. The recovery of radioactivity from the urine of rats dosed with [14C]DEHP was examined by solvent extraction and XAD-2 resin absorption procedures. Both of these procedures were inadequate for quantitative recovery of urinary metabolites required for subsequent mutagenicity testing using the Ames Salmonella/microsome procedure. Recoveries of less than 5% were observed using standard solvent extraction techniques whereas the XAD-2 adsorption technique gave about 67% at high resin/urine ratios. Treatment of the urine with beta-glucuronidase/aryl sulfatase did not affect these recoveries. The direct urine plating procedure represents a viable alternative to the above concentration procedures for this phthalate ester. The effects of L-histidine and the beta-glucuronidase/aryl sulfatase preparation on the background reversion frequencies of the Ames tester strains is discussed.

Animals↗
PubMed1985

Highly sulfated proteochondroitin sulfates synthesized in vitro by rat glomeruli.

A previous report from this laboratory (Kobayashi, S., Oguri, K., Kobayashi, K. and Okayama, M. (1983) J. Biol. Chem. 258, 12051-12057) indicated that isolated rat glomeruli synthesized three species of sulfated glycoconjugates in vitro, namely, sulfated glycoproteins, proteoheparan sulfates and proteochondroitin sulfates. In the present study, the proteochondroitin sulfates, which showed the greatest incorporation of [35S]sulfate among the three sulfated glycoconjugates, were isolated and characterized. Radiolabeled tissue proteochondroitin sulfates were clearly separated on Sepharose CL-6B into three components with partition coefficients (Kd) of 0.16, 0.22 and 0.58, and medium proteochondroitin sulfates were separated into two components with Kd values of 0.33 and 0.62. When the chondroitin sulfate chains released by alkaline borohydride treatment were analyzed by digestion with chondroitinase AC-II, chondroitinase ABC, chondro-6-sulfatase and chondro-4-sulfatase, the results showed that all the samples contained glucuronosyl-N-acetylgalactosamine (chondroitinase AC-II-susceptible sequences, 72-86%) and iduronosyl-N-acetylgalactosamine (chondroitinase ABC-susceptible sequences, 14-28%), containing 4-sulfated N-acetylgalactosamine (50-70%) and 4,6-disulfated N-acetylgalactosamine (30-50%). On two-dimensional electrophoresis on cellulose acetate, all samples gave a single spot which closely coincided with chondroitin sulfate E of squid cartilage in electrophoretic mobility. These results indicated that the chains were highly sulfated chondroitin sulfates containing glucuronic acid and iduronic acid residues.

Animals↗
PubMed1993

Ascorbate-2-sulfate sulfohydrolase in fish and mammal. Comparative characterization and possible involvement in ascorbate metabolism.

1. The new assay conditions were determined for crude and purified enzyme ascorbate-2-sulfate sulfohydrolase from liver tissues of two fish species and bovine. 2. The major departure from the existing indirect method, based on reduction of 2,6-dichlorophenolindophenol (DCIP) by released ascorbic acid and change from pink-blue to a colorless molecule, takes into account the shift of maximum absorbance of DCIP from 516 nm at pH 5.14 to 600 nm at pH 6.5. 3. The direct method is based on colorimetric assay of liberated ascorbic acid including correction for interfering substances. The optimum pH for both fish ascorbate sulfatases was 5.5. 4. The Km for bovine ascorbate sulfatase was confirmed to be approximately 7 mM at 37 degrees C. 5. Partly purified ascorbate-sulfate sulfohydrolase has a Km value in rainbow trout of 0.4 mM and it changes very little in the range of water temperatures characteristic for this stenothermic fish species. 6. In eurythermic chub, the Km values increased from 1.2 to 4.3 mM with rising temperatures.

2,6-Dichloroindophenol↗
PubMed2005

Optimization of conditions for the enzymatic hydrolysis of phytoestrogen conjugates in urine and plasma.

Optimal pH, temperature, and concentration of enzyme conditions for the rate of hydrolysis of five isoflavone conjugates (daidzein, O-desmethylangolensin, equol, genistein, and glycitein) and two lignans (enterodiol and enterolactone) from two biological matrices (urine and plasma) were studied using beta-glucuronidase from Helix pomatia. In addition, the use of mixtures of beta-glucuronidase and sulfatase enzymes from different sources was investigated to find enzyme preparations that contained lower amounts of naturally present phytoestrogens. Quantification of aglycones spiked with (13)C(3)-labeled internal standards was carried out by LC-MS/MS. In urine, all of the phytoestrogen conjugates hydrolyzed within 2h under standard hydrolysis conditions (24mul H. pomatia, pH 5, 37 degrees C). Hydrolysis rates were improved at 45 degrees C and by doubling the enzyme concentration and may be used to further reduce hydrolysis times down to 100min. In plasma, a 16-h hydrolysis was required to ensure complete hydrolysis of all conjugates. As with urine, the use of increased temperature or increased enzyme concentration reduced hydrolysis times for most analytes. However, the rate of hydrolysis in plasma was significantly slower than that in urine for all analytes except enterodiol, for which the reverse was true. Neither increased temperature nor increased enzyme concentration increased the rate of hydrolysis of enterolactone. Hydrolysis at pH 6 proved to be detrimental to hydrolysis of phytoestrogen conjugates, especially those in plasma. Other enzyme preparations from different sources, such as beta-glucuronidase from Escherichia coli, were found to contain lower amounts of contaminating phytoestrogens and showed increased enzyme activity for isoflavones, but lower activity for lignans, when used with other sulfatase enzymes. In addition, this involved complicating the analytical procedure through using mixtures of enzymes. Therefore, the use of beta-glucuronidase from H. pomatia combined with an enzyme "blank" to correct for phytoestrogen contamination was shown to be a suitable method for hydrolysis of phytoestrogens.

Animals↗
PubMed2006

A role for sulfation-desulfation in the uptake of bisphenol a into breast tumor cells.

Bisphenol A (BPA) is a widely used plasticizer whose estrogenic properties may impact hormone-responsive disorders and fetal development. In vivo, BPA appears to have greater activity than is suggested by its estrogen receptor (ER) binding affinity. This may be a result of BPA sulfation/desulfation providing a pathway for selective uptake into hormone-responsive cells. BPA is a substrate for estrogen sulfotransferase, and bisphenol A sulfate (BPAS) and disulfate are substrates for estrone sulfatase. Although the sulfated xenobiotics bind poorly to the ER, both stimulated the growth of receptor-positive breast tumor cells. Treatment of MCF-7 cells with BPAS leads to desulfation and uptake of BPA. No BPAS is found inside the cells. These findings suggest a mechanism for the selective uptake of BPA into cells expressing estrone sulfatase. Therefore, sulfation may increase the estrogenic potential of xenobiotics.

Benzhydryl Compounds↗
PubMed2005

Attack behaviors in mice: from factorial structure to quantitative trait loci mapping.

The emergence or non-emergence of attack behavior results from interaction between the genotype and the conditions under which the mice are tested. Inbred mice of the same strain reared or housed under conditions do not react the same way; reactions also vary according to the place selected for testing and the different opponents. A factor analysis showed that the attack behavior in non-isolated males, tested in neutral area covaried with high testosterone and steroid sulfatase and low brain 5-hydroxytriptamine (5-HT), beta-endorphin and Adrenocorticotropic Hormone (ACTH) concentration, whereas, for isolated males tested in their own housing cage, it covaried with high testosterone activity and low brain 5-HT concentration. A wide genome scan was performed with two independent populations derived from C57BL/6J and NZB/BlNJ, each being reared, housed and tested under highly contrasting conditions, as described above, and confronted with A/J standard males. Common Quantitative Trait Loci emerged for two rearing/testing conditions. For rattling latency we detected Quantitative Trait Loci on Mus musculus chromosome 8 (MMU8) (at 44, LOD score=3.51 and 47 cM, LOD score=6.22, for the first and the second conditions) and on MMU12 (at 39 cM, LOD score=3.69 and at 41 cM, LOD score=2.99, respectively). For the number of attacks, Quantitative Trait Loci were common: on MMU11 at 39 cM LOD score=4.51 and 45 cM, LOD score=3.05, respectively, and on MMU12 (17 cM, LOD score=2.71 and 24 cM, LOD score=3.10). The steroid sulfatase gene (Sts), located on the X-Y pairing region, was linked, but only in non-isolated males, tested in neutral area for rattling latency, first attack latency, and number of attacks (LOD scores=4.9, 4.79 and 3.57, respectively). We found also that the Quantitative Trait Locus encompassing Sts region interacted with other Quantitative Trait Loci. These results indicate that attack behavior measured in different rearing and testing conditions have different biological and genetic correlates. This suggests that further explorations should be done with standardized tests and, in addition, with a wide range of tests, so as to gain an understanding of the true impact of genes or pharmacological treatments on specific categories of aggressive behavior.

Aggression↗
PubMed2004

Quantitative analysis of cresol and its metabolites in biological materials and distribution in rats after oral administration.

We investigated kinetics of p-cresol, m-cresol, and their glucuronide and sulfate metabolites in blood and organs of rats. We established a quantitative analysis method for the measurement of the concentrations of cresols. Endogenous beta-glucuronidase, an enzyme which hydrolyses the glucuronide, existed in rat organs, and it influenced the procedures for cresol hydrolysis of sulfatase. It was necessary for the quantitative analysis of cresol sulfate in organs to add the saccharolactone (d-saccharic acid 1,4-lactone) as an inhibitor for beta-glucuronidase. On the other hand, endogenous sulfatase did not interfere in the quantitative analysis of the glucuronide. It was found that cresol administered via the stomach tube diffuses directly through gastric and small intestinal walls because the unconjugate cresol concentrations were extremely high not only in the liver, but also in the spleen. The unconjugates of cresol in the liver, spleen and kidney were detected in high concentrations even when the unconjugates were not detected in the blood. m-Cresol was easily metabolized to sulfate, and the p-cresol to glucuronide in rats. The concentration ratios of m-cresol to p-cresol in blood and organs were different from the rate of the cresol soap solution that was administered. The pharmacokinetics was different between p-cresol and m-cresol in rats.

Administration, Oral↗
PubMed2004

Tissue-selective effects of tibolone on the breast.

Hormone treatment with an estrogen plus a progestagen (EPT) increases the risk of breast cancer. Both hormone activities are also induced by tibolone. In order to assess the breast safety of tibolone, it was evaluated in several pre-clinical models. The effects were inconclusive in breast cancer cell lines but, in various in vivo models, it did not stimulate the breast. In the 17,12-dimethylbenz(a)anthracene (DMBA) model, tibolone clearly inhibited the growth of breast tumors and, when given prophylactally, far less tumors developed. Ovariectomized monkeys showed no increase in the expression of the proliferation marker Ki67. The effects of tibolone and its metabolites on the steroid metabolizing enzymes in breast tissues were investigated in order to unravel its mode of action in the breast. Tibolone and its metabolites did not inhibit aromatase, but sulfatase was profoundly inhibited. The sulfated 3alpha-OH tibolone metabolite even showed irreversible inhibition of sulfatase. In addition, 17ss-hydroxysteroid dehydrogenase activities were slightly inhibited and sulfotransferase activity was stimulated at low concentrations. The consequence of these effects is that, for both endogenous estrogens and estrogenic-metabolites of tibolone, the equilibrium is preferential for the sulfated forms. The intracellular hormonal milieu tibolone and its metabolites also influence cellular homeostasis. It inhibits cell proliferation of normal breast epithelial cells and stimulates apoptosis. In this respect, tibolone behaves differently from estrogens. Clinical studies have shown that tibolone users experience less breast tenderness and do not show an increase in mammographic density as found with continuous combined EPT. The data concerning tibolone and breast cancer risk are inconclusive and require further investigation.

Bone and Bones↗
PubMed2005

Expression analysis of estrogen-metabolizing enzymes in human endometrial cancer.

Estrogen-dependent endometrial cancer is related to unopposed and prolonged estrogen stimulation. We examined the expression of estrogen-metabolizing enzymes in correlation with the ERalpha and ERbeta estrogen receptors in human endometrial Ishikawa adenocarcinoma cells and in endometrial cancer specimens and adjacent normal endometrium from the same patients. Real-time PCR analysis revealed that both estrogen receptors and selected estrogen-metabolizing enzymes were expressed in the Ishikawa cells and in endometrial tissue. We detected higher expression of ERalpha than ERbeta, higher expression of sulfatase than sulfotransferase and low expression of aromatase in the Ishikawa cells and the tissue, as well as higher levels of type 2 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in normal and diseased tissue than in the Ishikawa cells. When we compared the expression in endometrial cancer samples and in the adjacent normal endometrium, ERalpha and ERbeta, sulfatase and sulfotransferase were seen to be downregulated in the majority of the cancerous tissue specimens.

17-Hydroxysteroid Dehydrogenases↗