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Results for “Estrogens, Catechol”

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PubMed1986

Inhibition of the preovulatory prolactin surge in the rat by catechol estrogens: functional and temporal specificity.

Catechol estrogens, administered iv to cycling rats on the morning of proestrus, were able to block the preovulatory PRL surge on the afternoon of the same day. Only catechol estrogens with a low affinity for the estrogen receptor, such as 2-hydroxyestrone and 2-hydroxyestradiol-17 alpha were effective in this respect, while the estrogenic catechol estrogen 2-hydroxyestradiol was unable to influence the PRL surge. The effectiveness of the PRL surge abolition was highly dependent on the state of the endogenous estradiol levels at the time of administration. Only doses given just before the peak secretion of estradiol were effective in blocking the PRL surge. Despite similarities in the inhibition of the preovulatory LH and PRL surges by catechol estrogens, these are considered to occur by different mechanisms because the LH secretion is blocked by all catechol estrogens, while the PRL surge is affected only by catechol estrogens with no estrogen agonist properties. The catechol estrogen blockade of the PRL surge may have physiological parallels and provides a useful probe of the mechanisms of the estrogen-PRL axis.

Animals↗

PubMed1991

A method for estimating catechol estrogen metabolism from excretion of noncatechol estrogens.

The relationship of catechol estrogen metabolism to disease has seldom been investigated because of analytic difficulties. Estradiol (E2) and estrone (E1) are oxidized simultaneously at either ring A or ring D, and the rate of catechol estrogen formation (r2) is reciprocally related to the rate of 16 alpha-hydroxylation (r3). The rate of ovarian estrogen production (X10) can be summarized as to metabolic outcome: X10 = r10 + r2 + r3 + r(u), where r10 is the loss of E1 and E2 in urine, and ru is the fecal and urinary loss of unknown oxidative products. Assuming a constant r(u) between subjects: constancy of the X10 concentration between subjects during similar menstrual cycle phases. In the absence of xenobiotics, r2 x r3 are reciprocally interrelated: r2 x r3 = K (an oxidation constant whose limiting factor is the biologically available estrogen at the cell surface). To the extent that r10 approximates estrogens available for cellular metabolism, the rate of catechol estrogen metabolism may be determined from (Formula; see text) From published data K = 12.4 +/- 0.8 of the standard error of the mean. Pearson correlation coefficients between actual and estimated catechol estrogen excretion in groups of subjects ranged from 0.61 to 0.97 (median, 0.88). This method has been useful for clinical investigation of the relationship of catechol estrogen metabolism to disease until better methods to measure catechol estrogen directly are available.

Body Weight↗

PubMed1980

Comparative properties of the catechol estrogens, I: methylation by catechol-O-methyltransferase and binding to cytosol estrogen receptors.

Five catechol estrogens and two 2-methoxyestrogens were compared for their relative affinity of binding to hypothalamic, pituitary, and uterine cytosol estrogen receptors; and for the kinetics of the catechols' methylation by hepatic catechol-0-methyltransferase. All of the catechol estrogens tested have similar Km's for 0-methylation (9-14 muM). Estrogen receptor affinities, however, differ widely. In hypothalamus, for example, where estradiol-17 beta has a Kd of 0.039 +/- 0.008 nanomolar, 4-hydroxyestradiol also binds tightly (0.12 +/- 0.02 nM), 2-hydroxyestradiol and 4-hydroxyestrone with intermediate affinity (0.26 +/- 0.06 and 0.28 +/- 0.07 nM, respectively), and 2-hydroxyestrone and 2-hydroxyestriol much less well (1.68 +/- 0.79 and 1.27 +/- 0.26 nM, respectively). The binding of the 2-methoxyestrogens is extremely weak. These receptor affinities roughly parallel the potencies of these compounds in altering gonadotropin secretion.

2-Methoxyestradiol↗

PubMed1997

ESR identification of free radicals formed from the oxidation of catechol estrogens by Cu2+.

Catechol estrogens are genotoxic, indirectly through redox cycling mechanisms leading to oxidative DNA damage and directly by formation of quinone-DNA adducts. Previously, we demonstrated that Cu2+ can oxidize estradiol (E2) catechols, establishing a copper redox cycle leading to the formation of DNA strand breaks. The goal of this study was to use electron spin resonance techniques to identify the free radical intermediates formed. The 2- and 4-OH catechols of E2 and ethinyl estradiol (EE) were oxidized to semiquinone intermediates, stabilized by Mg2+, when incubated with Cu2+. The 4-OH-EE semiquinone decayed more slowly than the 2-OH-EE semiquinone. Using the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone, 4-OH-E2 plus Cu2+ generated hydroxyl radicals at a greater rate than 2-OH-E2 plus Cu2+. Formation of hydroxyl and methyl radical adducts was detected, using 5,5-dimethyl-1-pyrroline-N-oxide as the spin trap, when 2-OH-E2 was incubated with Cu2+ and 1% dimethyl sulfoxide. This was inhibited by the Cu1+ chelator bathocuproinedisulfonic acid and catalase. These data demonstrate that the oxidation of estrogen catechols by Cu2+ leads to a Cu-dependent mechanism of hydroxyl radical production via a hydrogen peroxide intermediate and suggest a mechanism for estrogen-associated site-specific DNA damage and mutagenesis.

Benzoquinones↗

PubMedDate not supplied

Synthesis and characterization of estrogen 2,3- and 3,4-quinones. Comparison of DNA adducts formed by the quinones versus horseradish peroxidase-activated catechol estrogens.

Catechol estrogens (CE) are among the major metabolites of estrone (E1) and 17 beta-estradiol (E2). Oxidation of these metabolites to semiquinones and quinones could generate ultimate carcinogenic forms of E1 and E2. The 2,3- and 3,4-quinones of E1 and E2 were synthesized by MnO2 oxidation of the corresponding CE, following the method for synthesizing E1-3,4-quinone [Abul-Hajj (1984) J. Steroid Biochem. 21, 621-622]. Characterization of these compounds was accomplished by UV, nuclear magnetic resonance, and mass spectrometry. The relative stability of these compounds was determined in DMSO/H2O (2:1) at room temperature, and the 3,4-quinones were more stable than the 2,3-quinones. The four quinones directly reacted with calf thymus DNA to form DNA adducts analyzed by the 32P-postlabeling method. The adducts were compared to those formed when the corresponding CE were activated by horseradish peroxidase (HRP) to bind to DNA. The E1- and E2-2,3-quinones formed much higher levels of DNA adducts than the corresponding 3,4-quinones. In addition, many of the adducts (70-90%) formed by the E1- and E2-2,3-quinones appeared to be the same as those formed by activation of 2-OHE1 or 2-OHE2 by HRP to bind to DNA. Little overlap was observed between the adducts formed by E1- and E2-3,4-quinones and HRP-activated 4-OHE1 and 4-OHE2. These results suggest that semiquinones and/or quinones are ultimate reactive intermediates in the peroxidatic activation of catechol estrogens.

Autoradiography↗

PubMed2004

In vitro model of mammary estrogen metabolism: structural and kinetic differences between catechol estrogens 2- and 4-hydroxyestradiol.

Estrogens and their oxidative metabolites, the catechol estrogens, have been implicated in the development of breast cancer; yet, relatively little is known about estrogen metabolism in the breast. To determine how the parent hormone, 17 beta-estradiol (E(2)), is metabolized, we used recombinant, purified phase I enzymes, cytochrome P450 (CYP) 1A1 and 1B1, with the phase II enzymes catechol-O-methyltransferase (COMT) and glutathione S-transferase P1 (GSTP1), all of which are expressed in breast tissue. We employed both gas and liquid chromatography with mass spectrometry to measure E(2), the catechol estrogens 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)), as well as methoxyestrogens and estrogen-GSH conjugates. The oxidation of E(2) to 2-OHE(2) and 4-OHE(2) was exclusively regulated by CYP1A1 and 1B1, regardless of the presence or concentration of COMT and GSTP1. COMT generated two products, 2-methoxyestradiol and 2-hydroxy-3-methoxyestradiol, from 2-OHE(2) but only one product, 4-methoxyestradiol, from 4-OHE(2). Similarly, GSTP1 yielded two conjugates, 2-OHE(2)-1-SG and 2-OHE(2)-4-SG, from the corresponding quinone 2-hydroxyestradiol-quinone and one conjugate, 4-OHE(2)-2-SG, from 4-hydroxyestradiol-quinone. Using the experimental data, we developed a multicompartment kinetic model for the oxidative metabolism of the parent hormone E(2), which revealed significant differences in rate constants for its C-2 and C-4 metabolites. The results demonstrated a tightly regulated interaction of phase I and phase II enzymes, in which the latter decreased the concentration of catechol estrogens and estrogen quinones, thereby reducing the potential of these oxidative estrogen metabolites to induce DNA damage.

Animals↗

PubMed1992

Borate and molybdate inhibition of catechol estrogen and pyrocatechol methylation by catechol-O-methyltransferase.

The possibility that boron and molybdenum anions can influence sex steroid metabolism by forming complexes with catechol estrogens has been studied in vitro. The formation of 2-methoxyestrone (2-OHE1 2-Me) from 2-hydroxyestrone (2-OHE1) by catechol-O-methyltransferase (COMT) was followed by measuring the transfer of the radiolabeled methyl group from S-adenosylmethionine. In the presence of both sodium tetraborate and sodium molybdate using a phosphate buffer medium, the formation of 2-OHE1 2-Me decreased as the anion:2-OHE1 molar ratio was increased. However, the reverse effect was observed when using a tris buffer medium and further investigation showed that phosphate and sulphate also enhanced COMT activity in a tris buffer medium. Boric acid affinity medium, used as a substitute for borate salt, also showed a negative relationship with enzyme activity in a phosphate buffer medium, and inhibition of methylation was more marked than with the free anion. Erythrocytes contain appreciable amounts of COMT, which is mostly responsible for the rapid O-methylation of catechol estrogens in blood. The methylation of a simple catechol compound, 1,2-dihydroxybenzene (pyrocatechol) was therefore studied using rat red blood cell lysates. Methylation was inhibited in a concentration-related manner by borate, as found in the studies of 2-OHE1. It is possible that high dietary intakes of boron or molybdenum could regulate the rate of catabolism, or even the metabolic fate of the major estrogens.

Animals↗

PubMed1985

Estrogen 2- and 4-hydroxylase activity, catechol estrogen formation, and implications for estrogen carcinogenesis in the hamster kidney.

Estrogen 2- and 4-hydroxylase (ESH), a microsomal enzyme which mediates the formation of catechol estrogens, has been studied in the kidneys of castrated male Syrian hamsters, a species uniquely susceptible to induction of renal carcinomas by both steroidal and stilbene estrogens. The apparent Km for estrone was 17.0 microM, and Vmax was 0.5 pmol per mg protein per min for ESH in renal microsomes derived from castrated hamsters. Different steroidal estrogen substrates exhibited decreasing catechol formation with hamster kidney microsomal preparations in the following order: estrone greater than d-equilenin greater than 17 beta-estradiol greater than equilin greater than ethynyl estradiol greater than estriol. Except for beta-dienestrol, the stilbene estrogens revealed levels of catechol formation that were similar to 17 beta-estradiol. These findings provide a rationale for the weak carcinogenic activity of ethynyl estradiol, estriol, and beta-dienestrol, since they were poor substrates for hamster renal ESH and for the relatively potent carcinogenic activity of the distal metabolite of diethylstilbestrol, indenestrol B/A, which exhibited substantial levels of o-hydroxylation when used as a substrate. Interestingly, ESH activity was significantly greater in the hamster kidney compared to corresponding rat tissue, and catechol estrogen formation was found to be 2.5- to 19-fold higher in the hamster kidney compared to the rat, using various steroidal and stilbene estrogen substrates. Moreover, the finding that a 3.5- to nearly 6-fold decrease, compared to untreated levels, in catechol formation in kidneys but not in livers of alpha-naphthoflavone-exposed hamsters, depending on the steroidal or stilbene estrogen substrate used, is consistent with the belief that the catechol estrogen pathway is pertinent to events leading to estrogen-induced renal tumorigenesis in the hamster.

Animals↗

PubMed2004

Strong inhibitory effects of common tea catechins and bioflavonoids on the O-methylation of catechol estrogens catalyzed by human liver cytosolic catechol-O-methyltransferase.

In the present investigation, we studied the inhibitory effects of three tea catechins [catechin, epicatechin, and (-)-epigallocatechin-3-O-gallate] and two bioflavonoids (quercetin and fisetin) on the O-methylation of 2- and 4-hydroxyestradiol (2-OH-E(2) and 4-OH-E(2), respectively) by human liver cytosolic catechol-O-methyltransferase (COMT). We found that catechin and epicatechin each inhibited the O-methylation of 2-OH-E(2) and 4-OH-E(2) in a concentration-dependent manner. The IC(50) values for inhibition of 2-OH-E(2) methylation by catechin and epicatechin were 14 to 17 microM and 44 to 65 microM, respectively, and their IC(50) values for inhibition of 4-OH-E(2) methylation were 5 to 7 microM and 10 to 18 microM, respectively. Our data showed that these two catechins had 2- to 6-fold higher inhibition potency for the O-methylation of 4-OH-E(2) than for the O-methylation of 2-OH-E(2). (-)-Epigallocatechin-3-O-gallate was found to have a distinctly high inhibition potency for the O-methylation of 2- and 4-OH-E(2) (IC(50) values of 0.04-0.07 microM and 0.2-0.5 microM, respectively). The crude extracts from green tea and black tea also showed very strong activity in inhibiting human liver COMT-mediated O-methylation of catechol estrogens. We also determined, for comparison, two common bioflavonoids (quercetin and fisetin) for their inhibitory effects on human liver COMT-mediated O-methylation of catechol estrogens. The IC(50) values for quercetin and fisetin were 0.9 to 1.5 microM and 3.3 to 4.5 microM, respectively, for inhibiting the O-methylation of 2-OH-E(2), and 0.5 to 1.2 microM and 2.6 to 4.2 microM, respectively, for inhibiting the O-methylation of 4-OH-E(2). Enzyme kinetic analyses showed that both tea catechins and bioflavonoids inhibited human liver COMT-mediated O-methylation of 4-OH-E(2) (a representative substrate) with a mixed mechanism of inhibition (competitive plus noncompetitive). In summary, the catechol-containing tea catechins and bioflavonoids are strong inhibitors of human liver COMT-mediated O-methylation of catechol estrogens. More studies are warranted to determine the extent of such inhibition in human subjects and the potential biological consequences.

Catalysis↗

PubMed1982

Effects of chronic treatment with thyroxine and estradiol on estrogen concentration in serum and on hepatic microsomal catechol estrogen formation in female rats.

The effects of chronic treatment with thyroxine (T4) and estradiol on hepatic microsomal metabolism of estrogens to catechol products were studied and the extent to which activity in vitro correlated with serum estradiol concentrations in vivo was assessed. Female rats were treated with either estradiol benzoate (EB; 56 micrograms/kg/day from silastic implants), T4 (50 micrograms/kg/day, s.c.) or combined EB + T4 for 35 days. Animals treated with EB + T4, but not T4 alone, showed a significant increase above controls both in the concentration of triiodothyronine in serum and food consumption. Serum concentrations of endogenous estradiol in untreated control and T4-treated animals were similar. Although both EB-treated groups received comparable doses of steroid from silastic implants, the concentration of estradiol in serum was 30% lower in EB + T4-treated animals than in animals treated with EB alone. Formation of catechol estrogen metabolites by hepatic microsomes was not significantly altered by EB and T4 administered separately, but enzyme activity was increased significantly with combined hormonal therapy. In contrast, microsomal hydroxylation of testosterone was not increased by treatment with EB + T4, data which suggest that total steroid hydroxylase activity was not enhanced by combined hormonal administration. Correlation analysis of microsomal catechol estrogen formation in vitro with serum concentrations of estradiol in vivo indicated related to the concentration of estrogen in serum only after coadministration of a low dose of T4 with EB.

Animals↗

PubMed2000

Quantitation of catechol estrogens and their N-acetylcysteine conjugates in urine of rats and hamsters.

A method for the analysis of N-acetylcysteine conjugates of catechol estrogens [catechol estrogen mercapturates (CE SRs)], which are likely to be urinary markers of estrogen-induced tumors, was established in this study. The characteristics of the method that was established were (1) cleanup of urine using the immunoaffinity column of CE SRs, (2) detection of catechol estrogens (CEs) and CE SRs by electrochemical detection, which provided the high specificity, and (3) stability of CE SRs through the cleanup. Using this method, the simultaneous quantitation of 2-hydroxy-17beta-estradiol (2-OHE(2)), 4-hydroxy-17beta-estradiol (4-OHE(2)), 2-hydroxyestrone (2-OHE(1)), 4-hydroxyestrone (4-OHE(1)), 2-hydroxyestrone 1-N-acetylcysteine thioether (2-OHE(1) 1SR), 2-hydroxyestrone 4-N-acetylcysteine thioether (2-OHE(1) 4SR), and 4-hydroxyestrone 2-N-acetylcysteine thioether (4-OHE(1) 2SR) in the range of 1-15 ng was performed. We first demonstrated the presence of CE SRs, 2-OHE(1) 1SR and 2-OHE(1) 4SR, in urine from rats treated intraperitoneally with 17beta-estradiol (E(2)) at a dose of 5 mg/kg. In female rats, the amount of 2-OHE(1) 1SR was several-fold greater than that of 2-OHE(1) 4SR, while the presence of 4-OHE(1) 2SR was not confirmed. The level of CEs and CE SRs in male rats was approximately (1)/(2)-(1)/(20) of that in female rats. The excretion rate following administration of 2-OHE(1) at 2 mg/kg and that following the administration of 4-OHE(1) at 2 mg/kg were different in female rats. In addition, 4-OHE(1) 2SR was present in the urine of male Syrian hamsters treated intraperitoneally with E(2), whereas it was absent in rats.

Acetylcysteine↗

PubMed1986

Carcinogenicity of catechol estrogens in Syrian hamsters.

Estradiol and other estrogens induce renal carcinoma in male Syrian hamsters. The mechanism of carcinogenesis still remains unclear. Activation of estrogens to catechol metabolites has in the past been postulated to play a role in estrogen-induced carcinogenesis. Therefore, the carcinogenic activity of catechol estrogens was investigated. After 175 days of treatment, 4-hydroxyestradiol was found to be as carcinogenic as estradiol in male Syrian hamsters (4/5 and 4/5 animals with kidney tumors, respectively). Animals treated with 2-hydroxyestradiol (0/5) or 2-methoxyestradiol (0/6) did not develop renal carcinoma. The catechol estrogens failed to be mutagenic in the Ames test (reversions of his- S. typhimurium to histidine prototrophy in the TA 100 strain). The lack of carcinogenic activity of 2-hydroxyestradiol was not due to a failure to stimulate estrogen-dependent tumor growth. Growth of H-301 cells, an estrogen-dependent hamster kidney tumor cell line, was supported in vivo by estrogens in the following order: estradiol greater than 4-hydroxyestradiol greater than 2-hydroxyestradiol. Stimulation of tumor growth by 2-methoxyestradiol was not detected. It was concluded that the carcinogenic activity of 4-hydroxyestradiol was consistent with a role of catechol metabolites in estrogen-induced carcinogenesis. However, the intrinsic carcinogenic or hormonal activity of 2-hydroxyestradiol probably can not be assessed accurately in vivo because of its rapid methylation and metabolic clearance.

Animals↗

PubMed1989

Comparison of assays for catechol estrogen synthase activity: product isolation vs radioenzymatic catechol-O-methyltransferase-coupled procedures.

Reported values for the activity of enzymes mediating catechol estrogen formation by hamster kidney and liver, measured by catechol-O-methyltransferase-coupled radioenzymatic assay, have been uniformly low and there have been marked discrepancies in values reported from different laboratories. Therefore, we examined the validity of the radioenzymatic assay used in these studies. NADPH-dependent estrogen 2- and 4-hydroxylase activity of hamster liver microsomes measured by radioenzymatic assay was comparable to that reported in the literature but at least one order of magnitude lower than that obtained with a direct product isolation assay. Several features of the radioenzymatic assay were identified which, together, contribute to the underestimation of enzyme activity. They include, incomplete protection from oxidative degradation of both the catechol estrogens generated and of the catechol-O-methyltransferase and assay conditions which are suboptimal for O-methylation of the catechol estrogens. We conclude that results obtained using the catechol-O-methyltransferase-based radioenzymatic assay can only be considered valid if a consistent stoichiometric relationship can be demonstrated between the amounts of catechol estrogens and their O-methylated products.

Animals↗

PubMed1977

Catechol estrogens: presence in brain and endocrine tissues.

Catechol estrogens have been identified and measured in rat brain and various endocrine tissues with the use of a sensitive radioenzymatic assay. The specificity of this assay was confirmed by thin-layer chromatography and mass spectral analysis of the reaction products. The concentration of catechol estrogens in the hypothalamus and pituitary are at least ten times higher than reported previously for the parent estrogens. Catechol estrogens have potent endocrine effects and, because of their normal occurrence in the hypothalamic-pituitary axis, they have an important role in neuroendocrine regulation.

Animals↗

PubMed1986

Purification and characterization of estrogen-2/4-hydroxylase activity from rabbit hypothalami: peroxidase-mediated catechol estrogen formation.

Estrogen-2/4-hydroxylase (E-2/4-H) activity of rabbit hypothalamic tissue was previously found to be localized in the soluble subcellular fraction. In the present study, the enzymatic activity responsible for catechol estrogen formation in this subcellular fraction of the rabbit hypothalamus was purified by ammonium sulfate fractionation, ion exchange chromatography, and chromatofocusing. E-2/4-H activity was found to be associated with a group of hemoproteins with peroxidase activity. The characteristics of this hypothalamic E-2/4-H activity were reestablished in light of a peroxidatic mechanism for catechol estrogen formation. Organic hydroperoxides stimulated E-2/4-H activity, presumably by serving as oxidizing cosubstrate required for peroxidase-mediated reactions. E-2/4-H activity in a 17,500 X g supernatant of hypothalamic tissue was linear with time for at least 10 min and with protein concentration to at least 100 micrograms/150 microliter. It displayed a pH optimum of 6 and an apparent Michaelis-Menten constant (Km) of 32 microM with respect to estradiol. The amounts of 4-hydroxyestradiol formed were comparable to those of 2-hydroxyestradiol. The characteristics established in this study for the peroxidase-type E-2/4-H were distinct from those of the particulate, NADPH-dependent 2-hydroxylases found in rat liver and in porcine blastocyst and ovary. These differences provide a basis for differentiating between the two types of enzymatic activity that can lead to catechol estrogen formation in vitro.

Animals↗

PubMed2002

Characterization of human soluble high and low activity catechol-O-methyltransferase catalyzed catechol estrogen methylation.

The major detoxification pathway of the carcinogenic catechol estrogens is methylation by catechol- -methyltransferase (COMT). It has been hypothesized that the enzyme encoded by the low-activity allele (COMT(L) ) has a lower catalytic activity for catechol estrogen methylation than that encoded by the high activity allele (COMT(H) ). We expressed and purified human soluble (S)-COMT(H) and S-COMT(L) in and characterized the methylation of 2- and 4-hydroxyestradiol (2- and 4-OH-E2). There were no differences between the kinetic parameters for COMT(H) and COMT(L). The kinetic parameters for S-adenosylmethionine (SAM), the methyl donor in these reactions, also did not differ for COMT(H) and COMT(L). S-adenosylhomocysteine, the demethylated SAM metabolite, inhibited methylation of the catechol estrogens in a non-competitive manner similarly for COMT(H) and COMT(L). Each COMT substrate tested inhibited the methylation of other substrates in a mixed competitive and non-competitive fashion similarly for COMT(H) and COMT(L). Furthermore, in cytosolic fractions of COMT(HH)(MCF-10A and ZR-75-1) and COMT(LL)(MCF-7 and T47D) human breast epithelial cell lines, no differences were detected between the kinetic parameters of COMT with respect to 2- and 4-OH-E2 methylation; nor were COMT protein levels associated with the COMT genotype. These data suggest that the decreased COMT enzymatic activity that has been detected in human tissue in association with the COMT(L) allele is not reflected by differences in the affinity or capacity of COMT(H) and COMT(L) for catechol estrogen methylation. These results raise the question of what accounts for the difference in COMT activity associated with the COMT(HH) and COMT(LL) genotypes in human tissue.

Base Sequence↗

PubMed2000

The catechol estrogen, 4-hydroxyestrone, has tissue-specific estrogen actions.

Recent data indicate that the catechol estrogen, 2-hydroxyestrone (2-OHE(1)), has no effect on any target tissue including bone, whereas 16 alpha-hydroxyestrone (16 alpha-OHE(1)) exerts tissue-selective estrogen agonist activity. The effect of the catechol estrogen, 4-hydroxyestrone (4-OHE(1)), putatively associated with tumorigenesis, has not been studied in the skeleton. The purpose of this study was to assess the effect of 4-OHE(1) on tibia, uterine and mammary gland histology and blood cholesterol in ovariectomized (OVX'd) growing rats. Ten-week-old female Sprague-Dawley rats were injected subcutaneously with 200 microg/kg BW per day with 4-OHE(1), 17 beta-estradiol (E(2)) or vehicle for three weeks. OVX resulted in uterine atrophy, increased body weight, radial bone growth and cancellous bone turnover, and hypercholesterolemia. E(2) prevented these changes with the expected exception that the subcutaneous infusion of this high dose of estrogen did not prevent the hypercholesterolemia. 4-OHE(1) prevented the increase in blood cholesterol and the increase in body weight. 4-OHE(1) appeared to have partial estrogen activity in the uterus; uterine weight and epithelial cell height were significantly greater than the OVX rats but significantly less (twofold) than the E(2) animals. Analysis of variance indicated that 4-OHE(1) slightly decreased the periosteal mineral apposition rate (P<0.05) compared with vehicle-treated rats but had no effect on double-labeled perimeter or bone formation rate. Similarly, 4-OHE(1) was a partial estrogen agonist on cancellous bone turnover. The data suggest that the catechol estrogen, 4-OHE(1), unlike 2-OHE(1), has estrogen activity. Furthermore, the profile of activity differs from that of 16 alpha-OHE(1). Our results suggest that estrogen metabolites may selectively influence estrogen-target tissues and, concomitantly, modulate estrogen-associated disease risk.

Animals↗

PubMedDate not supplied

The characteristic binding of catechol estrogens to estrogen receptors in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors.

The binding of catechol estrogens (2-hydroxyestrone, 4-hydroxyestrone, 2-hydroxyestradiol, and 4-hydroxyestradiol) to estrogen receptors in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumor cytosols was investigated. Cytosol estrogen receptors exhibited high affinities (Ka = 1.12-1.88 X 10(8) M-1) for all catechol estrogens as well as estradiol. The receptor level of catechol estrogens (46.1-97.5 fmol/mg protein) was 1.6-3.0 times higher than that of estradiol; especially the binding of 4-hydroxyestrone to estrogen receptors was the highest of all catechol estrogens and estradiol. In judging the receptor level of more than 20 fmol/mg protein to be positive, the binding of catechol estrogens to estrogen receptors was approximately correlated with that of estradiol. The positive receptor level of catechol estrogens was found in a half of tumor cytosols which showed the negative receptor level of estradiol. These results suggested that characteristic estrogen receptors indicating high affinities for catechol estrogens might be present in rat mammary tumor cytosols.

9,10-Dimethyl-1,2-benzanthracene↗