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PubMed1986

Relative binding of certain steroids of low polarity to human sex hormone-binding globulin: strong binding of 2-methoxyestrone, a steroid lacking the 17 beta-OH group.

The cross-reactivities for binding sites on human sex hormone-binding globulin (SHBG) of a number of steroids of low polarity, including progesterone and estrogen metabolites, were studied. Binding relative to testosterone (100%) was low (less than or equal to 3%) except for 2-methoxyestrone (81%), 3-acetoxyestradiol (16%), 4-methoxyestradiol (6%), 3 beta-hydroxy-5 beta-pregnan-3-one (5.8%), 5 alpha-dihydrodeoxycorticosterone (4.5%), deoxycorticosterone (4%), 20 alpha-hydroxy-5 alpha-pregnan -3-one (4%), 4-methoxyestrone (4%) and 5 alpha-dihydroprogesterone (3.5%). 2-Methoxyestrone is the only steroid lacking a 17 beta-hydroxyl group which binds to SHBG with strong affinity.

Binding, Competitive↗
PubMed1985

Modulation of nonspecific cell-mediated growth inhibition by estrogen metabolites.

Chronic exposure of mice to estrogens such as 17-beta estradiol and diethylstilbestrol inhibits natural killer cell-mediated cytotoxicity in vivo. In this report, we investigated the direct in vitro effects of 17-beta estradiol and its major metabolites on nonspecific effector cell function measured as the ability of naive lymphocytes to inhibit the growth of the YAC-1 lymphoma, a classical natural killer-sensitive target cell. Without exception, the effects of individual estrogen metabolites on the growth inhibitory properties of these cells were accompanied, at every concentration of compound, by identical effects on the blastogenic response of lymphocytes to the T cell lectin phytohemagglutinin. These observations suggested membrane-mediated immunomodulation of lymphocyte function by estrogen metabolites. As suggested by previous studies with quinone metabolites of benzene, the catechol estrogen metabolite 2-OH estrone was significantly more potent than the parent compound at suppressing lymphocyte functions in vitro; however, dosing regimens of 2-OH estrone that suppressed blastogenic response in vivo failed to inhibit nonspecific cell-mediated growth inhibition.

Animals↗
PubMed1987

Differences in the mechanism of the inhibitory actions of catecholestrogens, tamoxifen and high concentrations of estrogens on prolactin release by cultured rat pituitary tumor cells.

Chronic administration of the catecholestrogens 2-OH-estrone (2-OH1) and 2-OH-estradiol (2-OHE2), of tamoxifen and its metabolites and of high concentrations of estradiol have been previously shown to inhibit the growth of the estrogen/progesterone receptor-positive transplantable prolactin (PRL)-secreting rat pituitary tumor 7315a. The mechanism of action of these inhibitory effects on tumor growth is unknown. In the present study we investigated the direct effects of these compounds on PRL release by a tumor cell clone derived from the 7315a tumor. E2 stimulated PRL release in FCSABS (10% estrogen-stripped fetal calf serum)-cultured tumor cells in a biphasic manner: at low concentrations (0.1-100 nM) there was a dose-dependent stimulation of PRL release, which decreased in response to 1 microM E2 and which was greatly inhibited by 10 microM E2. Both 2-OHE2 (100 nM and 1 microM) and 2-OHE2 (1 microM) inhibited PRL release by FCS-cultured tumor cells. In FCSABS-cultured tumor cells, 0.1-10 nM 2-OHE1 and 1 microM 2-OHE2 inhibited PRL release, but 1-100 nM 2-OHE2 stimulated PRL release. Tamoxifen (TMX) and its metabolites dihydroxy (di-OH-TMX) and 4-hydroxytamoxifen (4-OH-TMX) inhibited PRL in a dose-dependent manner. The PRL release inhibiting effect of 4-OH-TMX was 100 times more potent that those of TMX and di-OH-TMX, which were similar in their effect. The inhibitory effects of micromolar concentrations of the catecholestrogens on PRL release could be overcome by estradiol, while the inhibitory effects of high concentrations of tamoxifen were not prevented by estradiol. Both "endogenous" (catecholestrogens) and "exogenous" (tamoxifen and its metabolites) antiestrogens and very high concentrations of estradiol directly inhibit PRL secretion by cultured pituitary tumor cells. The mechanism of their anti-tumor effects, however, seems to differ. The catecholestrogens have direct anti-estrogenic effects on cultured tumor cells, which can be antagonized by estradiol. The final effect of their mixed antagonistic/agonistic action depends on the presence or absence of estrogens in the culture medium. Tamoxifen also affects tumor growth probably mainly via a direct effect, partly involving anti-estrogenic and partly direct toxic effects.

Animals↗
PubMed2005

In vitro aromatic bioactivation of the weak estrogen E(2)alpha and genesis of DNA adducts.

Specific A-ring hydroxylated metabolites of 17beta-estrogens are known to be endogenous pro-carcinogens, more particularly the 4-hydroxylated forms of estrogens produced by cytochrome P4501B1. In this study, we investigated whether estradiol-17alpha, the main hepatic residue of estradiol-17beta in cattle treated for anabolic purposes with estradiol containing implants, could be significantly metabolized by human cells, and whether its aromatic metabolites could induce the formation of DNA adducts as estradiol-17beta and estrone do. First, using a human kidney adenocarcinoma cell line, which expresses specifically the cytochrome P4501B1, we showed that estradiol-17alpha is bioactivated into a mixture of 2- and 4-catechol estrogens leading to the corresponding methoxyestrogens unambiguously identified by LC-APCI-MS/MS. We then demonstrated that the 2- and 4-hydroxylated derivatives of estradiol-17alpha incubated under oxidative conditions with calf thymus DNA gave stable DNA adducts and abasic sites, respectively. From these results, we can consider that human cells expressing CYP1B1-dependent hydroxylation activities metabolize estradiol-17alpha at the same magnitude as estradiol-17beta and estrone, and that in oxidative conditions, the resulting aromatic metabolites can lead to the formation of both stable and unstable DNA adducts.

Adenocarcinoma↗
PubMed1979

pKa values of estrone, 17 beta-estradiol and 2-methoxyestrone.

The acid ionization constants of estrone (10.77), 17 beta-estradiol (10.71) and 2-methoxyestrone (10.81) have been determined spectrophotometrically and shown to be consistent with the additivity of substituent effects of the phenol ring. Previously published values for estrone (10.914) and 17 beta-estradiol (10.078) are shown to be incorrect, at variance with the established trend for phenols, and inconcsistent with the similarity of the compounds.

Estradiol↗
PubMed1997

New synthesis of delta 6-estrogens.

An efficient approach to synthesize delta 6-estrogens is described. The key steps in the synthesis are the introduction of a hydroxyl group at the C-6 position of a suitably protected estrogen using a superbase and subsequent dehydration with Martin sulfurane reagent or methyltriphenoxyphosphonium iodide. The two-step synthetic procedure readily gave the delta 6-estrogens in high yield.

Estradiol Congeners↗
PubMed2000

Inhibition of deoxyglucose uptake in MCF-7 breast cancer cells by 2-methoxyestrone and 2-methoxyestrone-3-O-sulfamate.

Most cancer cells are dependent on glucose uptake to fulfil their energy requirements. In the present investigation we have examined the ability of 2-methoxyestrone (2-MeOE1), 2-methoxyestradiol (2-MeOE2), 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE), and a number of related compounds, to inhibit 2-deoxy-D-[1-(3)H]-glucose uptake in MCF-7 breast cancer cells. Glucose uptake was shown to be linear with respect to cell number and time over a 5-35min period. 2-MeOE2, 2-MeOE1 and 2-MeOEMATE inhibited glucose uptake by 25-49% at 10 microM. 2-Hydroxyestradiol and estrone sulfate had little effect on glucose uptake, whereas estrone glucuronide inhibited uptake by 29%. There is evidence that 2-methoxyestrogens may exert an anti-mitotic effect on cells by stabilizing microtubules in a similar manner to that of paclitaxel. We therefore examined the effect of exposing cells to 2-MeOEMATE or paclitaxel for 24 h on basal or insulin stimulated glucose uptake. Using these conditions, 2-MeOEMATE and paclitaxel inhibited basal glucose uptake by 50 and 22%, respectively, and insulin stimulated uptake by 36 and 51%, respectively. The development of drugs that can inhibit glucose uptake could have therapeutic potential for the treatment of breast cancer.

2-Methoxyestradiol↗
PubMed1997

Effects of dietary broccoli on human drug metabolising activity.

Eighteen volunteers received 500 g fresh broccoli every day for 12 days after a 6-day period of standard diet. The activity of CYP1A2, CYP2E1 and the estrone 2 and 16alpha-hydroxylation were determined prior to and after the broccoli diet. The average activity of CYP1A2 and the average 2/16alpha-hydroxyestrone ratio were increased 19% (P < 0.0005) and 29.5% (P < 0.05), respectively; however, no effects were observed on the CYP2E1 activity.

Anticarcinogenic Agents↗
PubMed2003

The effects of 2-substituted oestrogen sulphamates on the growth of prostate and ovarian cancer cells.

The human endogenous metabolite 2-methoxyoestradiol (2-MeOE2) has been shown to inhibit the proliferation of breast cancer cells. We have previously shown that sulphamoylation of a series of 2-substituted oestrogens greatly enhances their ability to inhibit breast cancer cell proliferation and induce apoptosis. In this study, we have investigated the ability of a number of 2-substituted oestrogens and their sulphamoylated derivatives to inhibit the proliferation of two prostate cancer cell lines, an ovarian cancer cell line and its drug-resistant derivatives. 2-Methoxyoestrone, 2-ethyloestrone and 2-ethyloestradiol had little effect on the growth of the cell lines tested (IC(50)>10 microM). 2-MeOE2 did inhibit the growth of the cells (IC(50)<10 microM), but to a lesser extent than any of the sulphamoylated derivatives tested (IC(50)<1.0 microM). Cells treated with the sulphamoylated derivatives became detached and rounded, displaying a characteristic apoptotic appearance. FACS analysis revealed induced G(2)/M cell cycle arrest. Treatment of cells and subsequent drug removal indicated that the effects of the drugs on the cells were irreversible. Immunoblot analysis indicated that apoptosis may be induced by phosphorylation of BCL-2. From these studies, 2-substituted oestrogen sulphamates are emerging as a potent new class of drug that may be effective against AR+/AR- prostate and ovarian tumours, and against tumours that are resistant to conventional chemotherapeutic regimens.

2-Methoxyestradiol↗
PubMed1985

Reactivation of human placental 17 beta,20 alpha-hydroxysteroid dehydrogenase affinity alkylated by estrone 3-(bromoacetate): topographic studies with 16 alpha-(bromoacetoxy)estradiol 3-(methyl ether).

Estradiol 17 beta-dehydrogenase and 20 alpha-hydroxysteroid dehydrogenase, oxidoreductase activities copurified from the cytosol of human-term placenta as a homogeneous protein (native enzyme), were reactivated at equal rates to 100% activity following complete inactivation in the presence of cofactor (NADPH) with the affinity alkylator estrone 3-(bromoacetate). Reactivation was accomplished by base-catalyzed hydrolysis of steroidal ester-amino acid linkages in the enzyme active site. The rate of enzyme reactivation was pH dependent. In identical studies without NADPH, only 12% of the original enzyme activity was restored. Completely reactivated enzyme was repurified by dialysis. Enzyme in control mixtures (control enzyme) that contained estrone in place of alkylator was treated the same as the reactivated enzyme. Reactivated enzyme exhibited a 6.0-fold lower affinity for common substrates, a 1.8-fold lesser affinity for NAD+ and NADH, and the same affinity for NADP+ and NADPH compared to control enzyme. In incubations that included NADPH, the reactivated enzyme maintained full activity during a 20-h second exposure to estrone 3-(bromoacetate), but in identical incubations without NADPH, the reactivated enzyme was rapidly inactivated at the same rate as the control and native enzymes. The control and reactivated enzymes were inactivated at equal rates by 16 alpha-(bromoacetoxy)estradiol 3-(methyl ether) in the presence or absence of cofactor (NADP+) and exhibited similar Kitz and Wilson inhibition constants for this affinity alkylator. Estrone 3-(bromo[2'-14C]acetate) incubated with native enzyme and NADPH produced radiolabeled 3-(carboxymethyl)histidine and S-(carboxymethyl)cysteine.(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxysteroid Dehydrogenases↗
PubMed2001

In vitro generation of peroxynitrite by 2- and 4-hydroxyestrogens in the presence of nitric oxide.

Estrogen metabolism is altered in most, if not all, breast cancer tumors. These alterations primarily lead to the formation of the catechol estrogen metabolites, 2- and 4-hydroxyestrogens, which can generate superoxide anion radicals (O(2)(*)(-)) through the redox cycling of semiquinone/quinone derivatives. In breast cancer cells, the activity of nitric oxide synthase is also frequently elevated, resulting in an increased level of exposure to nitric oxide ((*)NO). Since (*)NO rapidly reacts with O(2)(*)(-) to produce the peroxynitrite anion (ONOO(-)), this study was undertaken to determine whether ONOO(-) can be generated when 2- and 4-hydroxyestrogens are incubated in vitro with (*)NO donor compounds. Using dihydrorhodamine 123 as a specific probe for ONOO(-) formation, a ratio of 100 microM dipropylenetriamine NONOate (DPTA/NO) to 10 microM 4-hydroxyestradiol (4-OHE(2)) gave an optimal ONOO(-) production of 11.9 +/- 1.9 microM (mean +/- SD). Quantification of ONOO(-) was not modified by mannitol, supporting the idea that the hydroxyl radical was not involved. This production of ONOO(-) required the presence of the catechol structure of estrogen metabolites since all methoxyestrogens that were tested were inactive. Hydroxyestrogen metabolites derived from estradiol showed the same efficiency in producing ONOO(-) as those originating from estrone. With DPTA/NO, the 4-hydroxyestrogens generated 30-40% more ONOO(-) than the 2-hydroxyestrogens. Optimal production of ONOO(-) was assessed with DPTA/NO and diethylenetriamine NONOate (initial (*)NO generation rates of 0.76 and 0.08 microM min(-1), respectively). With faster (*)NO-releasing compounds, such as diethylamine NONOate and spermine NONOate, lower levels of ONOO(-) were detected. These data suggest that once the optimal concentration of (*)NO was obtained, the reaction between (*)NO and 4-OHE(2) was saturated. The excess of (*)NO would probably react with aqueous oxygen to form nitrite (NO(2)(-)). Since the third-order reaction rate for the reaction between 2(*)NO and O(2) is 2 x 10(6) M(-2) s(-1), it can therefore be suggested that the reaction between (*)NO and 4-OHE(2) occurs at a faster rate.

Chromatography, High Pressure Liquid↗