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PubMed2003

A preliminary study of the effect of fluoxetine treatment on the 2:16-alpha-hydroxyestrone ratio in young women.

Cytochrome P450 isoenzymes are known to contribute to estrone metabolism. The authors hypothesized that fluoxetine, a known inhibitor of multiple P450 isoenzymes including 3A4, 2C9, and 2D6, would affect estrone metabolism, altering the 2-hydroxyestrone:16-alpha-hydroxyestrone (2OHE1:16OHE1) ratio. In this preliminary study, four of eight recruited women with regular menstrual cycles, aged 21-37 years, completed a 24-hour urine collection prior to initiation of fluoxetine therapy and after at least 5 weeks of antidepressant treatment. In three of the four women who were nonsmokers, the 2OHE1:16OHE1 ratio was significantly higher after 5 weeks of fluoxetine therapy (pretreatment, 2.08 +/- 0.11; posttreatment, 3.50 +/- 0.46; paired Student's t-test P = 4.72, P = 0.021).

Adult↗
PubMed2000

Effect of dietary soy isoflavone aglycones on the urinary 16alpha-to-2-hydroxyestrone ratio in C3H/HeJ mice.

Estradiol is metabolized through two mutually exclusive pathways. 2-Hydroxyestrone (2-OHE,) is antiestrogenic, while 16alpha-hydroxyestrone (16alpha-OHE1) is a potent estrogen. It is suggested that a high urinary 16alpha-OHE1-to-2-OHE1 rato is a biomarker of increased mammary tumor risk. Mice were fed one of the test diets for 21 days. Indole-3-carbinol (2,500 mg/kg diet) increased the cytochrome P-450 content of hepatic microsomes and liver weight and reduced the urinary 16alpha-OHE1-to-2-OHE1 ratio in comparison with the respective value in the control mice. Fermented soy extract (100, 200, or 400 mg isoflavonoid/kg diet), genistein (200 mg/kg diet), and daidzein (200 mg/kg diet) each reduced the urinary 16alpha-OHE1-to-2-OHE1 ratio without increasing the cytochrome P-450 content of hepatic microsomes or liver weight. The combination of genistein and daidzein (100 mg and 100 mg/kg diet) did not have a synergistic effect on the reduction in urinary 16alpha-OHE1-to-2-OHE1 ratio. These data suggest that the soy isoflavonoid aglycones genistein and daidzein and indole-3-carbinol each exert a cancer-preventive effect by shifting metabolism away from the production of genotoxic metabolites toward the production of inactive metabolites.

Animals↗
PubMed1979

Absence of measurable 2-hydroxyestrone in the rat brain: evidence for rapid turnover.

The free 2-hydroxyestrone content of female rat brains was measured by two independent methods, including a direct radioimmunoassay and enzymatic conversion to stable O-methylated derivatives followed by a specific radioimmunoassay for the latter. The sensitivities of the two procedures were 10 pg and 5 pg respectively and the recoveries were greater than 85%. Neither assay method was able to detect any measurable endogenous 2-hydroxyestrone in the female rat brain at any stage of the ovulatory cycle. It is suggested that a high turnover rate of 2-hydroxyestrogens in the rat brain precludes the accumulation of detectable quantities of these metabolites in central tissues.

Animals↗
PubMed1980

Suppression of prolactin and gonadotropin secretion in post-menopausal women by 2-hydroxyestrone.

An infusion of 2-hydroxyestrone given to estrogen primed post-menopausal women resulted in a rapid and total suppression of serum prolactin. Serum LH responded with an initial rise followed by a 30% decrease below baseline values. Serum FSH exhibited a significant suppression below preinfusion levels. The catechol estrogen had no effect on serum LH, FSH and PRL in post-menopausal women who were not pretreated with estrogens. This impact of 2-hydroxyestrone on pituitary hormone secretion provides for the physiological role of this non-uterotropic estrogen in the neuroendocrine mechanisms of the human.

Estrone↗
PubMed1998

Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk.

Metabolism of estradiol occurs via two mutually exclusive hydroxylative pathways, yielding metabolites of divergent biological properties. 2-hydroxyestrone (2OHE1) is anti-estrogenic while 16 alpha-hydroxyestrone (16 alpha OHE1) is a potent estrogen. The ratio of 2OHE1 to 16 alpha OHE1 (2/16 alpha-OHE1 ratio) represents the net in vivo estrogenic activity. In this study, we sought to determine if the urinary 2/16 alpha-OHE1 ratio could be a predictor of breast cancer risk and the factors which influence this ratio. Variables analysed included age at diagnosis, menopausal status, parity, use of oral contraceptives, body mass index, serum levels of insulin-like growth factor-I (IGF-I), IGF binding proteins (BPs) and the presence of breast cancer. Serum and urine were collected from 65 breast cancer patients and 36 controls after an overnight fast. Urinary estrogen metabolites were measured by enzyme immunoassays while serum levels of IGF-I, BP-1 and BP-3 were determined by immunoradiometric assays. 2OHE1 levels and 2/16 alpha-OHE1 ratios were significantly lower (P < 0.05) while 16 alpha OHE1 levels were higher (P < 0.01) in cancer patients. Multiple linear regression analysis showed that levels of urinary metabolites were influenced by parity and breast carcinoma. 2/16 alpha-OHE1 ratio correlated positively with serum BP-3 level (P = 0.03). By multiple logistic regression, 2/16 alpha-OHE1 ratio was the most significant factor predictive of breast cancer. The odds ratio for women with higher 2/16 alpha-OHE1 ratios was 0.10 (0.03-0.38, 95% confidence interval). In conclusion, the profile of urinary estradiol metabolites was distinctly altered in breast cancer patients. In addition, BP-3 may be a potential mechanism by which estradiol metabolites influence breast cancer progression. As 16 alpha OHE1 has been shown to initiate neoplastic transformation of mammary epithelial cells, the 2/16 alpha-OHE1 ratio may serve as a biomarker of increased risk of breast cancer.

Age Factors↗
PubMed1975

The excretion of 2-hydroxyestrone during the menstrual cycle.

A double isotope derivative determination technique was developed to investigate the excretion of 2-hydroxyestrone inhuman menstrual cycle. The method is highly specific, accurate and precise within the range of 0.2-20 nmol 2-hydroxyestrone/20ml of urine. The amounts of 2-hydroxyestrone excreted during menstrual cycle varied between 10 (proliferation phase) and 60 mug/24 h urine (ovulatory peak), which is comparable to that of estriol, supposed hitherto to be the main excretion product of estrogen metabolism.

Estrone↗
PubMed1975

[Excretion of estriol, estetrol, 16-epi-estriol, 16-keto-estradiol and 16-hydroxyestrone in the 24-hour urine of pregnant women in the last trimester].

In this publication a method is given which allows simultaneous estimation of estriol, estetrol, 16-epiestriol, 16-ketoestradiol and 16-hydroxyestrone in urine of pregnant women. First conjugates are precipitated with ammoniumsulfate and hydrolyzed. Then the steroids are extracted and converted to azodyes by reacting with the diazonium salt dark blue r. After separation by thin layer chromatography the azodyes are measured by remission analysis with a chromatogramm spectrophotometer. From the data obtained from 66 cases norm groups were set up for the excretion of the steroids in the 3rd trimester of pregnancy. In the last month of pregnancy the average excretion, expressed in % of excreted estriol, is as follows: estetrol 5,7%, 16-epiestriol 3,1%, 16-ketoestradiol 7,0%, 16-hydroxyestrone 5,3%.

Adult↗
PubMed1985

Determination of 16 alpha-hydroxyestrone by radioimmunoassay in systemic lupus erythematosus.

A radioimmunoassay for the feminizing metabolite 16 alpha-hydroxyestrone was applied to a variety of sera from healthy volunteers, patients with active or inactive systemic lupus erythematosus (SLE), and patients with other rheumatic diseases. A significant increase in this metabolite was detected in patients with SLE, especially those with active disease, compared with normal controls (P less than 0.001). SLE patients were categorized as having either active or inactive disease by clinical and laboratory criteria. Many patients who had clinically and serologically active disease were found to have normal levels of this estrogenic metabolite, and several explanations for these differences are explored in this report. Despite a poor correlation of hormone levels with age, antibody levels, or complement levels in patients with SLE, those patients with the highest levels of hormone were among those whose disease was clinically most active.

Adult↗
PubMed1983

Characterization of antisera to the addition product formed by the nonenzymatic reaction of 16 alpha-hydroxyestrone with albumin.

16 alpha-Hydroxyestrone (16 alpha OHE) has been shown previously to react nonenzymatically with proteins via a Heyns rearrangement of a Schiff base intermediate. Albumin modified by the addition of 16 alpha OHE is immunogenic, despite a relatively low molar substitution. High-titre antisera can be elicited which have a very high affinity toward the estrogen hapten. Cross-reactivity analysis reveals a high specificity for the phenolic A-ring and a lack of specificity to chemical substituents in the D-ring, the site of covalent linkage. The antisera reacts equally well with 16 alpha OHE-peptides as with 16 alpha OHE-lysine, suggesting the utility of this antisera in analyzing either enzymatically or chemically hydrolyzed proteins for the presence of 16 alpha OHE adducts. Immunochemical analysis of proteins modified by 16 alpha OHE may provide insight into the pathogenesis of systemic lupus erythematosus, an autoimmune disease in which elevated levels of 16 alpha OHE are known to occur.

Animals↗
PubMed1987

Inhibition of the preovulatory LH surge after a catecholestrogen (2-hydroxyestrone) antiserum injection in the third ventricle of cycling female rats.

Administration of a catecholestrogen (2-hydroxyestrone, 2-OHE1) antiserum (2-OHE1-AS) in the third ventricle of cycling female rats, on the morning of proestrus, leads to a significant reduction in the afternoon LH surge. These responses are dose-dependent and can be observed even when the 2-OHE1-AS is injected on the diestrus morning. Almost similar results were obtained with an antiserum against 17 beta-estradiol (17 beta-E2). Nevertheless, the fact that the central immunoneutralization of 2-OHE1 impedes the preovulatory surge of LH at a time of high peripheral levels of 17 beta-E2 strengthens the idea of a specific role for 2-OHE1 in the control of cycling LH release.

Animals↗
PubMed1999

Effect of metal ions on the stable adduct formation of 16alpha-hydroxyestrone with a primary amine via the Heyns rearrangement.

16alpha-Hydroxyestrone (16alpha-OHE1), one of the major estrogen metabolites in humans that may plays a role in cell transformation, has been found to form stable adducts with nuclear proteins. The mechanism for the formation of a stable covalent adduct of 16alpha-OHE1 with protein has been postulated via the Heyns rearrangement after Schiff base formation. The Heyns rearrangement on the steroidal D-ring alpha-hydroxyimine was investigated using 17-(2-methoxyethylimino)estra-1,3,5(10)-triene-3,16alpha-dio l as a model intermediate. Rates of the Heyns rearrangement and hydrolysis of the steroidal a-hydroxyimine were determined by a high-performance liquid chromatography (HPLC) simultaneously. The Heyns rearrangement was demonstrated to be optimum at pH 6.2 and the reaction rate at physiological pH, 7.3-7.5, was more than 90% of that at the optimum pH. On the other hand, modulator(s) to the reactions were also examined. According to our previous finding of the proton-mediated mechanism of the Heyns rearrangement, the effects of cationic metal ions on the reactions were examined with 29 metal chlorides. Five metal ions, Pt4+, Cu2+, Ni2+, Co2+, and Mn2+, suppressed the formation of Heyns product significantly while Fe2+, Y3+, Gd3+, and Er3+ slightly increased it. The suppression rate was synergistically enhanced by the combination of Pt4+ with Co2+, Cu2+, or Ni2+. These results suggest the five metal ions, Pt4+, Cu2+, Ni2+, Co2+, and Mn2+, reduce the formation of the Heyns product in vivo and, therefore, would be useful tools to clarify the implication of the stable adduct formation of 16alpha-OHE1 with protein.

Cations↗
PubMed2003

Comparative effects of long-term continuous release of 16 alpha-hydroxyestrone and 17 beta-estradiol on bone, uterus, and serum cholesterol in ovariectomized adult rats.

16Alpha-hydroxyestrone (16alpha-OHE(1)), an endogenous estrogen metabolite, is associated with increased bone density in postmenopausal women. This study was designed to evaluate the long-term activity of this metabolite on bone, uterus, and serum cholesterol in an animal model for postmenopausal bone loss. A preliminary dose-response study performed in weanling rats determined 2000 microg/kg/day to be the optimal dose of 16alpha-OHE(1) for studying estrogenic effect on bone. The long-term experiment was performed in 6-month-old animals that were either sham-operated or OVX. The OVX rats were implanted sc with 60-day continuous-release carrier, 17beta-estradiol (E(2)) (33 microg/kg/day) or 16alpha-OHE(1) pellets (2000 microg/kg/day). OVX decreased uterine weight, increased body weight, serum cholesterol, and all dynamic bone histomorphometric measurements in cortical and cancellous bone, and resulted in a 54% bone loss at the tibial metaphysis. E(2) completely prevented OVX-induced bone loss, suppressed bone turnover, and induced uterine hypertrophy and hypercholesterolemia. 16alpha-OHE(1) acted as an E(2) agonist on bone, suppressing bone formation and resorption. However, the estrogen metabolite lowered serum cholesterol and was only a partial E(2) agonist on uterine weight and epithelial cell height. These results suggest that 16alpha-OHE(1) is an estrogen agonist on bone and may be responsible, in part, for the cholesterol-lowering activity attributed to estrogen. As a consequence of its skeletal effects, older women who produce high levels of 16alpha-OHE(1) could have a lower risk for developing postmenopausal osteoporosis than women who produce less-active estrogen metabolites.

Animals↗
PubMed1985

Interaction of histones with estrogens. Covalent adduct formation with 16 alpha-hydroxyestrone.

Disturbed estrogen metabolism leading to increased 16 alpha-hydroxyestrone (16 alpha-OHE) has been described in patients with systemic lupus erythematosus and mammary carcinoma. Previous studies showed the formation of covalent complexes between 16 alpha-OHE and nonspecific cellular membrane proteins. The present study is concerned with the interaction of 16 alpha-OHE and histones. Covalent adduct formation between 16 alpha-OHE and individual histones was maximal with H1 histone. Other endogenous estrogens such as estrone, estradiol, and estriol did not interact with histones and form covalent adducts, nor did they interfere with the interaction of 16 alpha-OHE with these nuclear proteins. The evidence supports that the adduct formation between 16 alpha-OHE and histones proceeds via a stabilized Schiff base and subsequent rearrangement. This adduct formation which may have in vivo analogues may represent a mechanism for cellular transformation by this estrogen metabolite.

Estradiol↗
PubMedDate not supplied

Oxidative transformation of 2-hydroxyestrone. Stability and reactivity of 2,3-estrone quinone and its relationship to estrogen carcinogenicity.

The carcinogenicity of estrogens in rodents and man has been attributed to either alkylation of cellular macromolecules and/or redox-cycling, generation of active radicals, and DNA damage. Metabolic activation of estradiol leading to the formation of catechol estrogens is believed to be a prerequisite for its genotoxic effects. 4-Hydroxyestradiol, although not 2-hydroxyestradiol, is a potent inducer of tumors in hamsters. Previous studies have shown that 3,4-estrone quinone can redox-cycle and is capable of inducing exclusively single strand DNA breaks in MCF-7 breast cancer cells, as well as react with various nucleophiles (thiol, imidazole, amino, phenolate, and acetoxy) to give Michael addition products. These results support the possible involvement of 3,4-catechol/quinone estrogens in estrogen's carcinogenicity. To explain the decreased carcinogenicity of 2-hydroxyestrogens, the reactions of 2,3-estrone quinone (2,3-EQ) with nucleophiles were investigated. Reactions of 4-methylimidazole with 2,3-EQ gave a complex mixture of products leadng to the formation of the catechol, C-O dimerization product, and a 1,6-Michael addition product identified as the 1-(4-methylimidazolo)-2-hydroxyestrone. Reactions of 2,3-EQ under mildly basic conditions with either ethyl phenolate or acetate gave several products which were characterized as the C-O and C-C dimers, catechol, and 3,5-dihydroxy-1(10), 3-estradiene-2, 17-dione. No Michael addition products were detected under these experimental conditions. The same products were also observed during the synthesis of 2,3-EQ, which led us to postulate that the lack of carcinogenicity of 2-hydroxyestrogens may be related to the increased reactivity and decreased stability of the quinone under physiological conditions. These results are contrasted with those obtained with 3,4-EQ which is much more stable and therefore could diffuse from the site of formation to the target tissue. These results along with rapid methylation and clearance may be very likely explanations for the decreased carcinogenicity of 2-hydroxyestrogens.

Carcinogens↗
PubMed1988

Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization.

The interactions of 16 alpha-hydroxyestrone (16 alpha-OHE1), a metabolite of estradiol (E2), with estrogen receptors (ERs) were compared in this study to the classic E2-receptor mechanism in human breast cancer cells MCF-7 in culture. When MCF-7 cells were incubated with radioinert 16 alpha-OHE1 or its 3H-labeled form for 4 weeks, the estrogen bound extensively and irreversibly in a time-dependent fashion to nuclear protein species that correspond to the ER. Here we show that the interactions of 16 alpha-OHE1 with the ER are different from those of E2 with the receptor. Dissociation of tritiated E2-ER or 16 alpha-OHE1-ER complexes, salt extraction, DNase and proteinase K digestion, and ethanol treatment demonstrated that the binding of 16 alpha-OHE1 to the ER corresponds to two different forms: a classical noncovalent interaction similar to that of E2, and a covalent adduct formation between the metabolite and the ER. These complexes localized preferentially in nuclear matrix components as revealed by cell fractionation and probing with a monoclonal anti-ER antibody. [3H]16 alpha-OHE1-ER complexes analyzed by polyacrylamide gel electrophoresis demonstrated a radiolabeled band at approximately 66 kDa that was absent when the exposure of cells was done in the presence of E2 in competition and that was also absent in [3H]E2 incubations. The present results when considered together with our previous findings of elevated activities of estrogen 16 alpha-hydroxylase, the enzyme responsible for the formation of 16 alpha-OHE1, in breast cancer patients and in women at enhanced risk for the disease, suggest that covalent modification of the ER may be one mechanism of malignant transformation in estrogen target tissues.

Antibodies, Monoclonal↗
PubMed1992

Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells.

BACKGROUND: Estrogens are potent mammary tumor promoters influencing post-initiation events via epigenetic mechanisms. The upregulation (i.e., induction) of the C16 alpha-hydroxylation pathway during 17 beta-estradiol (E2) biotransformation has been associated with mammary cell transformation. The action of E2 metabolites on tumorigenic transformation, however, is poorly understood. PURPOSE: The newly established mammary epithelial cell line C57/MG, derived from the C57BL mouse strain, was used to examine whether E2 or its metabolites, 16-hydroxyestrone (16 alpha-OHE1) and estriol (E3), function as initiators of mammary cell transformation. METHODS: DNA repair (hydroxyurea-insensitive thymidine uptake), estrogen metabolism (3H exchange to form 3H2O), hyperproliferation (increased cell number), and acquisition of anchorage-independent growth (soft-agar colonies) were used as quantitative end points to measure the relative extent of transformation. RESULTS: Treatment of cells with 200 ng/mL 16 alpha-OHE1 resulted in a 55.2% increase in DNA repair synthesis, a 23.09% increase in proliferative activity, and a 18-fold increase in the number of soft-agar colonies, relative to the solvent controls (P less than .0001). The extent of upregulation of the three end points was similar to that induced by the genotoxic mammary carcinogen 7, 12-dimethylbenz[a]anthracene (DMBA, positive control). DMBA treatment also upregulated the ratio of 16 alpha/C2 hydroxylation of E2 leading to increased formation of 16 alpha-OHE1. E2 and E3 were not effective in upregulating these markers for transformation. CONCLUSION: These results demonstrate that in nontransformed C57/MG cells, 16 alpha-OHE1 may function as an initiator, perturbing the intermediate biomarkers for preneoplastic transformation.

Animals↗
PubMed1984

The reaction of 16 alpha-hydroxyestrone with erythrocytes in vitro and in vivo.

16 alpha-Hydroxyestrone (16 alpha OHE ) has been shown previously to react with albumin, forming stable covalent adducts with lysine residues. The incubation of [3H]16 alpha OHE with whole blood also results in the incorporation of tritium into cells, with the rate of incorporation paralleling that of 16 alpha OHE -protein adduct formation. 32% of erythrocyte acid-precipitable radioactivity was found to be present within membrane proteins and electrophoresis demonstrated that several of these proteins are modified by [3H]16 alpha OHE . Membrane proteins from the red cells of ten individuals were reduced with sodium borohydride, acid hydrolyzed, and the 16 alpha OHE -lysine adducts purified by hydrophobic chromatography and reverse-phase high-pressure liquid chromatography. The amount of these adducts was quantitated by radioimmunoassay and found to be five times higher than the plasma levels of free 16 alpha OHE . This reflects most likely the accumulation of 16 alpha OHE -protein adducts during the course of the red cell life. Quantitation of 16 alpha OHE -protein adducts with other cellular proteins may contribute to our understanding of systemic lupus erythematosus, an autoimmune disease in which elevated levels of 16 alpha OHE occur.

Blood Proteins↗
PubMed1980

Suppression of prolactin secretion in normal young women by 2-hydroxyestrone.

The nonuterotropic natural estrogen 2-hydroxyestrone administered to normal young women results in a prompt and profound suppression of serum prolactin in most of the subjects. With the exception of dopamine, this is the only endogenous material known to strongly inhibit prolactin secretion, and its action suggests that the physiological regulation of prolactin by estrogens in the human is dual in nature, consisting of stimulation by estradiol and inhibition by its catechol estrogen metabolite.

Adult↗