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PubMed1990

In vitro synthesis of 16 alpha-hydroxyestrone by female rat liver microsomes: its possible role in the etiology of breast cancer.

Liver homogenates from female rat strains (Sprague-Dawley, Wistar and Fisher) were incubated in a NADPH regenerating medium in the presence of labelled and unlabelled estrone. Liver microsomes isolated from male rats and female mice were used as positive controls. Using HPLC and paper chromatography, under the experimental conditions used it was found that liver homogenates from female rats were able to convert estrone to various metabolites such as 16 alpha-hydroxyestrone. In a mutagenicity assay (Ames test), with 16 alpha-hydroxyesterone as test substance, two strains (TA98 and TA1538) of the five strains tested showed a 2-3-fold increase in the number of his+ revertants relative to the control values. Estrone did not cause any mutagens in the test used. It is concluded that female rats are able to synthesize 16 alpha-hydroxyestron in vitro. Whether this compound is risk factor for breast cancer remains unclear.

Animals↗

PubMed1980

Low plasma levels of 2-hydroxyestrone are consistent with its rapid metabolic clearance.

Published plasma levels of the catechol estrogen 2-hydroxyestrone (2-OHE1) are comparable to those of estrone and estradiol. In light of the very high (40,000 L/d) metabolic clearance rate of 2-OHE1, these concentrations imply unreasonable production rates. We therefore re-examined plasma 2-OHE1 levels using a modified radioimmunoassay procedure. Plasma samples are extracted with ethyl acetate and passed over a short column of LH-20 Sephadex before equilibration with an antiserum directed against a 2-hydroxyestrone-17-(O-carboxymethyl)oxime-bovine serum albumin conjugate. Plasma 2-OHE1 concentrations are indistinguishable from blank (< 15 pg/ml) in men and non-pregnant women, but rise to approximately 200 pg/ml during pregnancy. These values for 2-OHE1 levels are consistent with the rapid metabolic clearance of this catechol estrogen.

Adolescent↗

PubMed1983

Identification of 6 alpha- and 7 alpha-hydroxyestrone as major metabolites of estrone and estradiol in porcine uterus.

Polar metabolites extracted from the effluents of viable porcine uterine strips superfused with either 6,7-3H-estrone or 6,7-3H-estradiol were identified as a 1:1 mixture of 6 alpha-hydroxyestrone and 7 alpha-hydroxyestrone by paper chromatography in various systems, derivatization and crystallizations to a constant specific activity. The hydroxylated compounds are the only derivatives detected after estrone superfusion. The major metabolite of estradiol released in short-time experiments is estrone followed by its 6 alpha- and 7 alpha-hydroxylated derivatives.

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↗

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↗

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↗

PubMed1981

Metabolic clearance rate and uterotropic activity of 2-hydroxyestrone in rats.

2-Hydroxyestrone (2-OHE1) has much lower uterotropic potency than might be predicted from its uterine estrogen receptor affinity. 2-OHE1 displaces saturably bound [3H]estradiol from rat uterine cytosol with a competitive inhibition constant of 8.6 nM, while the dissociation constant for 17 beta-estradiol (E2) is 0.42 nM. From this ratio of binding affinities, one would expect some agonist or antagonist activity of 2-OHE1 to be apparent at doses roughly 20-50 times the minimum effective dose of E2. Instead, at doses of 2-OHE1 1000 times an effective dose of E2, no uterotropic effect was observed. When 2-OHE1 was injected together with E2 at dose ratios of 500:1, there was no antagonism of the effect of E2. To examine this discrepancy, the plasma MCRs (MCRpS) of E2 and 2-OHE1 were determined by continuous infusion techniques. Plasma concentrations of 2-OHE1 and E2 during control and infusion periods were measured by RIAs. The MCRp of 2-OHE1 averaged 50,000 ml/h, more than 100 times that of E2 (approximately 400 ml/h). The extraordinarily high MCRp of 2-OHE1 may explain the failure to observe any biological effects of this catechol estrogen, even at high doses. This rapid metabolism, presumably occurring in the blood compartment, should be considered in handling blood samples for RIA and in devising studies of the actions of catechol estrogens.

Animals↗

PubMed1983

Radioimmunoassay of 2-hydroxyestrone in plasma during the estrous cycle of the rat: interrelationships with estradiol, progesterone, and the gonadotropins.

A RIA for 2-hydroxyestrone (2-OHE1) in rat plasma has been developed. The assay employs an antiserum that is specific for catechol estrogens. Specificity is further ensured by purification of plasma extracts on Sephadex LH-20 columns before RIA. Blood was collected at 0 C in the presence of ascorbic acid to prevent oxidation. Under these conditions, the conversion of 2-OHE1 to methylated derivatives was found to be negligible. Plasma 2-OHE1, LH, FSH, PRL, estradiol, and progesterone were measured at 3-h intervals throughout the 4-day estrous cycle of the rat. The 2-OHE1 concentration varied from undetectable to 11 pg/ml plasma. No clearly defined relationship with the other hormones analyzed was observed. Thus, it is unlikely that changes in circulating 2-OHE1 levels are involved in the regulation of the gonadotropin surge and ovulation.

Animals↗