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PubMed1990

Cloning and expression of human liver UDP-glucuronosyltransferase in COS-1 cells. 3,4-catechol estrogens and estriol as primary substrates.

The human cDNA clone, UDPGTh-2, encoding a liver UDP-glucuronosyltransferase (transferase) was isolated from a lambda gt11 cDNA library by hybridization to the mouse transferase cDNA clone, UDPGTm-1 (Kimura, T., and Owens, I. S. (1987) Eur. J. Biochem.168, 515-521). The two clones have nucleotide sequence identities in the coding region of 74%. UDPGTh-2 encodes a 529-amino acid protein with an NH2 terminus membrane-insertion signal peptide and a carboxyl terminus membrane-spanning region. There are three potential asparagine-linked glycosylation sites at residues 67, 68, and 315. In order to establish substrate specificity, the clone was inserted into the pSVL vector (pUDPGTh-2) and expressed in COS-1 cells. The presence of a transferase with Mr congruent to 52,000 in transfected cells cultured in the presence of [35S]methionine was shown by immunocomplexed products with goat antimouse transferase IgG (Mackenzie, P. I., Hjelmeland, L. H., and Owens, I. S. (1984) Arch. Biochem. Biophys. 231, 487-497) and protein A-Sepharose and analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. The transferase is a glycoprotein as indicated by a shift in Mr congruent to 3000-4000 when expressed in the presence of tunicamycin. Sixty potential substrates were tested using cells transfected with pUDPGTh-2. The order of relative substrate activity was as follows: 4-hydroxyestrone greater than estriol greater than 2-hydroxyestriol greater than 4-hydroxyestradiol greater than 6 alpha-hydroxyestriol greater than 5 alpha-androstane-3 alpha,11 beta,17 beta-triol = 5 beta-androstane-3 alpha,11 beta,17 beta-triol. There were only trace amounts of glucuronidation of 2-hydroxyestrone and 2-hydroxyestradiol, and, in contrast to other cloned transferases, no glucuronidation of either the primary estrogens/androgens (estrone, 17 beta-estradiol/testosterone, androsterone) or any of the exogenous substrates tested. A Lineweaver-Burk plot of the effect of 4-hydroxyestrone concentration on the velocity of glucuronidation shows an apparent Km of 13 microM. The unique specificity of this transferase for 3,4-catechol estrogens and estriol suggests it may play an important role in regulating the level and activity of these potent and active estrogen metabolites.

Amino Acid Sequence↗
PubMed1979

Alterations of estrogen metabolism in systemic lupus erythematosus.

Estradiol metabolism in 10 patients with systemic lupus erythematosus (SLE) and 29 normal controls was studied by measurement of urinary metabolites after injection of labeled 3H-estradiol. Patients with SLE manifested increased 16-hydroxylation of estrone. Diseases men differed from diseases women to the extent that only 16 alpha-hydroxyestrone was elevated in men, whereas women had elevations of both 16 alpha-hydroxyestrone and estriol. These data suggest that patients with SLE have abnormal patterns of estradiol metabolism, leading to increased estrogenic activity.

Adolescent↗
PubMed2002

Catecholestrogen sulfation: possible role in carcinogenesis.

A growing body of evidence supports the hypothesis that estrogens can be carcinogens as a result of their conversion to genotoxins after biotransformation to form the catecholestrogens (CEs) 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2). CEs can then undergo further metabolism to form quinones that interact with DNA to form either stable or depurinating adducts. These events could potentially be interrupted by the sulfate conjugation of both the parent estrogens and/or the CEs. We set out to determine whether CEs can serve as substrates for sulfate conjugation, and-if so-which of the growing family of human sulfotransferase (SULT) isoforms are capable of catalyzing those reactions. We determined apparent K(m) values for 10 recombinant human SULT isoforms, as well as the three most common allozymes for SULT1A1 and SULT1A2, with 2-OHE1, 2-OHE2, 4-OHE1, and 4-OHE2, and with the endogenous estrogens, estrone (E1) and 17beta-estradiol (E2), as substrates. With the exception of SULT1B1, SULT1C1, and SULT4A1, all of the human SULTs studied catalyzed the sulfate conjugation of CEs. SULT1E1 had the lowest apparent K(m) values, 0.31, 0.18, 0.27, and 0.22 microM for 4-OHE1, 4-OHE2, 2-OHE1, and 2-OHE2, respectively. These results demonstrate that SULTs can catalyze the sulfate conjugation of CEs, and they raise the possibility that individual variation in this pathway for estrogen and CE metabolism as a result of common genetic polymorphisms could represent a risk factor for estrogen-dependent carcinogenesis.

Carcinogens↗
PubMed2001

Urinary excretion pattern of catecholestrogens in preovulatory LH surge during the 4-day estrous cycle of rats.

The formation of catecholestrogens represents a major pathway of estrogen metabolism and catecholestrogens are regarded as the main estrogen metabolite in non-pregnant state of various mammalian systems. In the present investigation, level of 2-hydroxyestrone, the major catecholestrogen excreted in rat urine, was measured by radioimmunoassay following acid hydrolysis and column chromatography of the 24-h urine samples of female Sprague Dawley non-pregnant rats during their 4-day estrous cycle. Urinary levels of estrone, estradiol and estriol were measured. Unlike the plasma level, urinary 2-hydroxyestrone showed a marked increase during the pre-ovulatory LH surge suggesting a plausible role of catecholestrogen in the mid-cycle elevation of the gonadotropin level in normal cycling rats.

Animals↗
PubMed1983

The role of 2-methoxyestrone in estrogen action.

The plasma and tissue concentrations of 2-methoxyestrone (2-MeOE1) and 2-hydroxyestrone (2-OHE1) were measured in immature rats. The plasma levels of 2-MeOE1 were found to be high at birth and to decrease through puberty, when the low levels found in the adult rats were achieved. 2-OHE1 was undetectable in the plasma and brain, and barely detectable in the uterus and liver. 2-MeOE1 was undetectable in the brain and uterus, but high in the liver. The affinity of 2-MeOE1 and 2-OHE1 for rat alpha-fetoprotein was found to be low, while the affinity of estradiol, estrone, 4-hydroxyestrone, and 4-fluoroestradiol was high. This data suggests that 2-OHE1 and 2-MeOE1 would be available to estrogen target tissues in the fetal and neonatal rat. Although these metabolites lack uterotropic activity they are capable of acting in the liver. It is suggested that the plasma 2-MeOE1 of neonatal rats acts as a prohormone capable of stimulating the liver and other estrogen target tissues which possess demethylating enzymes. It is pointed out that unlike estradiol the non-steroidal estrogens such as diethylstibestrol (DES) lack the ability to form two sets of catechol and guaicol metabolites, i.e. "C-2" and "C-4" metabolites with their different biological characteristics are not formed by DES.

Aging↗
PubMed1989

Cigarette smoking alters hepatic estrogen metabolism in men: implications for atherosclerosis.

Studies of steroids and plasma lipoproteins in male cigarette smokers reveal that smoking is associated with an increase in peripheral estrogens and a decrease in high-density lipoprotein-cholesterol (HDL-C). We hypothesized that the lower HDL-C in this setting results in part from induction of the hepatic metabolic pathway that inactivates estrogen. This pathway, estradiol 2-hydroxylation, produces the peripherally inactive catechol estrogens 2-hydroxyesterone and 2-methoxyestrone. We used an in vivo radiometric method to assess 2-hydroxylation in 20 male smokers and 16 nonsmokers. The extent of the reaction (+/- SEM) was significantly higher among the smokers (43.3% +/- 1.9% v 24.6% +/- 1.9%, P less than .001). Smokers also excreted more urinary 2-hydroxyestrone (10.4 +/- 1.3 micrograms/g creatinine v 6.3 +/- 0.73 micrograms/g in nonsmokers, P = .011). The ratio of urinary 2-hydroxyestrone to estriol was higher on average among smokers (1.46 +/- 0.19 v 0.81 +/- 0.11, P = .006), and individual values correlated well with the radiometric test (r = .71, P less than .002). These data indicate that smoking is associated with significantly increased estrogen 2-hydroxylation in men. Preliminary evidence suggests that the smoking effect on C-2 hydroxylation may be opposed by ethanol. Elevated 2-hydroxylation in smokers, in the setting of modestly increased peripheral estrogens and a net decrease in HDLC, may be explained by the fact that lipoprotein synthesis and estrogen 2-hydroxylation both occur predominantly in the liver. Thus, greater metabolic inactivation of hepatic estrogens in male smokers could reduce HDLC, despite a modest rise in circulating hormone levels.

Adult↗
PubMed1976

Convenient large scale preparation of catechol estrogens.

2-Hydroxyestrone, 2-hydroxyestradiol-17beta, 2-hydroxy-17alpha-ethynylestradiol, 2-hydroxyestriol, 4-hydroxyestrone, 4-hydroxyestradiol-17beta, 4-hydroxy-17alpha-ethynylestradiol and 4-hydroxyestriol are prepared on a preparative scale from the corresponding aminophenols using a new inverse oxidation procedure. By the synthesis described both the 2- and 4-hydroxylated estrogens are available in high yields.

Catechols↗
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↗
PubMed1994

Catechol estrogen production in rat microsomes after treatment with indole-3-carbinol, ascorbigen, or beta-naphthaflavone: a comparison of stable isotope dilution gas chromatography-mass spectrometry and radiometric methods.

Compounds like indole-3-carbinol (I3C) have been shown to increase catechol estrogen formation and reduce mammary tumor incidence in mice. These compounds may exert a protective effect for breast cancer development by decreasing the overall estrogen pool available for the formation of 16 alpha-hydroxyestrone (16 alpha-OHE1), a metabolite that retains significant estrogenic activity, may be mutagenic and could represent a potential carcinogenic intermediate of estradiol degradation. I3C and ascorbigen originate from the breakdown of glucobrassicin. We have compared the inductive effects of I3C with ascorbigen and beta-naphthaflavone (Bnf) in microsomes from rats pretreated with these compounds using isotope dilution GC-MS and a radiometric method. Incubated microsomes from rats pretreated with I3C and ascorbigen yielded high levels of 2-hydroxyestradiol (2-OHE2) that were comparable to levels induced by Bnf and were significantly above control group levels (p < 0.005). Absolute values determined by the radiometric method were approximately 40% lower than 2-OHE2 concentrations determined by GC-MS, although the relative changes in each group were the same. These differences may be attributed to the radiolabel becoming trapped in microsomal intermediates in the sequence leading to tritium entering the aqueous compartment. Both ascorbigen- and Bnf-treated animals exhibited significant increases in 2-hydroxyestrone (2-OHE1) (p < 0.05). The ability of ascorbigen to induce estradiol C-2 hydroxylation has not been previously reported. Based on these data, we speculate that ascorbigen will act as an anticarcinogenic agent and will inhibit or reduce the incidence of mammary tumor formation.

Animals↗
PubMed1996

Synthesis of N-acetylcysteine conjugates of catechol estrogens.

The synthesis of N-acetylcysteine conjugates of 2-hydroxyestrone (2-OHE1) and 4-hydroxyestrone (4-OHE1) is described. The reaction of estrone 2,3-quinone with N-acetylcysteine provided 2-OHE1 and its C-4 and C-1 thioether conjugates in a ratio of 1:1, while estrone 3,4-quinone with N-acetylcysteine gave 4-OHE1 and its C-2 thioether conjugate as a sole product. Their structures were characterized by inspection of NMR spectra, chemical derivatization (methylation and acetylation), and comparison with the reactivity of 4-bromoestrone 2,3-quinone or 2-bromoestrone 3,4-quinone toward N-acetylcysteine.

Acetylcysteine↗
PubMed2004

Synovial fluid estrogens in rheumatoid arthritis.

Experimental and clinical evidence suggest that immune reactivity is modulated by gender. Immune reactivity is greater in females than in males and lymphocytes and monocytes from female subjects shows higher antigen presenting activity and mitogenic responses. Steroid hormones can be converted along defined pathways to downstream hormones in the periphery. The conversion of dehydroepiandrosterone (DHEA) in target macrophages leads to an increase of downstream effector hormones (including estrogens), which may be an important factor for local immunomodulation at least in RA synovitis. The presence in the RA synovial fluids (SF) of an altered sex hormone balance resulting in lower immunosuppressive androgens and higher immunoenhancing estrogens, might determine a favorable condition for the development of the immuno-mediated RA synovitis and synovial hyperplasia. The increased estrogen concentration observed in RA SF of both sexes are characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, that is a mitogenic and proliferative endogenous hormone. In contrast to 16alpha-hydroxylated estrogens, the 2-hydroxylated forms inhibit growth promoting effects of E2 and were found low in RA SF. Therefore, dose-related conversion to pro- or anti-inflammatory downstream metabolites of estrogens might support the dual role of estrogens (pro or anti-inflammatory) for example during estrogen replacement therapy, depending on local concentration (i.e. SF in RA) of 16alpha-hydroxyestrone or 2-hydroxyestrogens.

Arthritis, Rheumatoid↗
PubMed2005

Urinary estrogen metabolites, prostate specific antigen, and body mass index among African-American men in South Carolina.

INTRODUCTION: Estrogen metabolites have been linked to risk of breast cancer, and we were interested in whether they are associated with prostate specific antigen (PSA) and other factors associated with prostate cancer. African-American (AA) men in South Carolina have among the highest prostate cancer rates in the world, and thus provide an ideal population in which to investigate this hypothesis. METHODS: We recruited AA men attending prostate cancer screenings in and around Columbia, South Carolina. Because very few men had elevated PSAs, we restricted our study to the 77 men whose PSA was below the cutpoint used by the screening program to indicate need for diagnostic workup. These men provided spot urine samples and answered demographic and lifestyle questions including self-reported body weight, height, exercise, tobacco use, medications, cancer history and age. Levels of urinary 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), and their ratio (2/16) and blood PSA levels were determined. RESULTS: After adjusting for a statistically significant interaction between age and BMI, we found a reduction of 14.2% in 2-OHE1 for each 1.0 ng/ml increase in PSA (p=0.05). For obese AA men only (BMI> or =30 kg/m2), 2-OHE1 increased by 36% for each decade of age (p=0.009). CONCLUSIONS: Estrogen metabolites may be related to PSA level in AA men. Older men with BMIs greater than 30 kg/m2 had an unexpected increase in 2-OHE1, suggesting a dysregulation of this estrogen metabolism pathway. Further studies of estrogen metabolites may provide insights into prostate cancer risk factors.

Adult↗
PubMed2004

Serum steroid hormones, sex hormone-binding globulin concentrations, and urinary hydroxylated estrogen metabolites in post-menopausal women in relation to daidzein-metabolizing phenotypes.

Equol and O-desmethylangolensin (O-DMA) are products of bacterial metabolism of daidzein, an isoflavone in soybeans; thus, the presence or absence of equol and/or O-DMA in urine is a marker of particular intestinal bacteria profiles. Plasma hormone concentrations may be lower in pre-menopausal women who harbor the bacteria capable of producing equol (equol producers) compared to women who do not (equol non-producers). We evaluated concentrations of serum hormones, sex hormone-binding globulin (SHBG), and urinary 2-hydroxyestrone (2-OH E(1)) and 16alpha-hydroxyestrone (16alpha-OH E(1)) in relation to equol-producer and O-DMA-producer phenotypes in 89 post-menopausal women. Follicle stimulating hormone (FSH) was 23% greater in O-DMA-producers compared to non-producers (P = 0.04). No significant differences in serum estrogens, androgens, metabolic hormones, or SHBG were observed in relation to either daidzein-metabolizing phenotype. Compared with non-producers within each phenotype, age-adjusted 2-OH E(1):16alpha-OH E(1) was 27% greater (P = 0.06) in equol-producers and 9% greater (P > 0.10) in O-DMA-producers, and 2-OH E(1) concentrations were 24% greater in equol producers (P = 0.07) and 42% greater in O-DMA producers (P = 0.02). No significant differences in 16alpha-OH E(1) were observed in relation to either phenotype. These results suggest that interindividual variability in intestinal bacteria may be related to differences in products of hormone metabolism in post-menopausal women.

Aged↗
PubMed2003

Urinary estrogen metabolites and breast cancer: differential pattern of risk found with pre- versus post-treatment collection.

INTRODUCTION: The products of estrogen metabolism may affect breast carcinogenesis. The 16alpha-hydroxyestrone (16-OHE) metabolite has a higher affinity for the estrogen receptor (ER) than the 2-hydroxyestrone (2-OHE) metabolite, while conjugated 2-OHE metabolite may inhibit angiogenesis. We investigated the association between the relative concentrations of these metabolites in urine (2-OHE/16-OHE) and breast cancer in a case-control study of Chinese women living in Shanghai. METHODS: Incident breast cancer cases between 25 and 65 years of age (n=110) were identified from hospital or population tumor registries in Shanghai, China. Controls (n=110) were randomly selected from a complete registry of the Shanghai population, and individually matched to cases by menopausal status, age, and pre-treatment or post-treatment urine collection time. Urine samples were collected prior to any breast cancer treatment or surgery among 78 case-control pairs, while urine was collected after surgery, and perhaps other treatments, among 32 case-control pairs. A commercial enzyme-immunoassay kit was used to measure urinary estrogen metabolite concentrations. Conditional logistic regression was used to calculate odds ratios summarizing the 2-OHE/16-OHE and breast cancer association within subjects providing either pre-treatment or post-treatment urine samples. RESULTS: Subjects with a higher urinary 2-OHE/16-OHE ratio were less likely to be diagnosed with breast cancer, but only when urine samples were collected prior to breast cancer treatment (OR(Tertile3(T3)versusTertile1(T1))=0.5, 95% CI (0.2, 1.1)). In contrast, a higher 2-OHE/16-OHE ratio was significantly associated with breast cancer among subjects providing urine specimens after treatment initiation (OR(T3versusT1)=8.7, 95% CI (1.6, 47.1)). This observed cross-over modification occurred within both pre-menopausal and post-menopausal women, and independent of body mass index or recent dietary intake. CONCLUSION: Cross-study differences in urine collection protocols may explain observed inconsistencies in the 2-OHE/16-OHE and breast cancer association. Our case-control analysis using pre-treatment urine samples suggested that a lower 2-OHE/16-OHE ratio was associated with an increased risk of pre-menopausal and post-menopausal breast cancer diagnosis among Chinese women.

Adult↗
PubMed1999

The effect of diurnal and menstrual cyclicity and menopausal status on estrogen metabolites: implications for disease-risk assessment.

It has been proposed that the ratio of two estrogen metabolites, 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), may represent a marker to predict a woman's risk for developing breast cancer and other estrogen-related disease. The present studies evaluated the potential confounders of type of sample, diurnal rhythm, menstrual cycle phase, and menopausal status on the ratio of 2/16alpha-OHE1 using an urine-based monoclonal antibody enzyme immunoassay. Two initial studies to compare a 24-h urine collection with a first-morning void and to evaluate diurnal variation were performed. Subsequently, urine samples were collected every other day for 2 months from five premenopausal subjects to assess the impact of the menstrual cycle. Spot urine samples were then obtained from a total of 67 pre, peri-, early post-, and late post-menopausal women to assess the effect of menopausal status. No significant difference in the ratio of 2/16alpha-OHE1 was found between a 24-h and first-morning void or over a 24-h period. No significant difference in the mean ratio of 2/16alpha-OHE1 was found with the menstrual phase. Intra-individual variability was observed in the ratio of 2/16alpha-OHE1, which was attributable to small fluctuations in the small denominator, 16alpha-OHE1. No difference in the ratio of 2/16alpha-OHE1 was observed in groups of women of different menopausal status. The data suggest that a first-morning void is representative of a 24-h collection and that the 2/16alpha-OHE1 ratio is constant throughout a 24-h period. Moreover, menstrual phase and menopausal status do not appear to significantly influence the ratio of 2/16alpha-OHE1.

Adult↗
PubMed2003

Estrogens in female thyroid cancer: alteration of urinary profiles in pre- and post-operative cases.

To evaluate the potential effect of estrogens in premenopausal female thyroid cancer, the concentrations of 14 estrogens were quantitatively determined in the urine of pre- and post-operative patients with thyroid papillary cancer (18 patients case, 26 approximately 54 years) and normal female subjects (20 cases, 31 approximately 52 years). The highly sensitive gas chromatography-mass spectrometry-selected ion-monitoring method was used for estrogens analysis. And an estrogen-oxidative metabolism and 16alpha-hydroxyestrone to 2-hydroxyestrone (16alpha-OH E1/2-OH E1) which is the two primary and competing site of estrogen-oxidation, were determined. Catechol estrogens, including 2-OH E1, were also increased without significant changes of the other estrogen metabolites in pre-operative patients with thyroid papillary cancer compared with normal subjects. The lowest mean value of 16alpha-OH E1/2-OH E1 was remarked in pre-operative patients, and it was significantly different from the ratio of post-operative cases. As a result, it is suggested that the increase of 2-hydroxylation in estrogen metabolism may have a significant association with female thyroid cancer.

Adult↗
PubMed2002

Estradiol metabolism and malignant disease.

Endogenous estradiol metabolism results in metabolic products that are still capable of exerting various biological, partially estrogen-antagonistic actions. This indicates that the effects of estradiol in carcinogenesis may depend on individual variations of metabolic breakdown of estradiol. The aim of this paper is to review and discuss the available data relating to stimulatory and inhibitory properties of estradiol metabolites on carcinogenesis. Results of main D-ring metabolites and main A-ring metabolites are presented. There are indications that the endogenous production of growth influencing estradiol metabolites may be elevated in neoplasias. Some results in this respect are available for stimulating tumor growth for the D-ring metabolite 16-hydroxyestrone and the A-ring metabolites 4-hydroxyestrone and 4-hydroxyestradiol. Inhibitory effects exist for the A-ring metabolite 2-methoxyestradiol (2-ME). So far, only a few metabolites have been studied closely for their influence on carcinogenesis. There is also a dearth of data on the intracellular metabolism of estradiol in neoplastic tissues. Knowledge of the metabolites may reveal new approaches to diagnosis and treatment of malignant diseases. 2-ME has already shown actions in pharmacological dosages which led already to a first trial to prove its suitability for treating human breast cancer.

2-Methoxyestradiol↗
PubMed1998

Estrogenic and antiestrogenic activities of 16alpha- and 2-hydroxy metabolites of 17beta-estradiol in MCF-7 and T47D human breast cancer cells.

The comparative mitogenic activities of 17beta-estradiol (E2) and four metabolites, 2-hydroxyestradiol (2-OHE2), 2-hydroxyestrone (2-OHE1), 16alpha-hydroxyestradiol (16alpha-OHE2) and 16alpha-hydroxyestrone (16alpha-OHE1) were determined in estrogen receptor (ER)-positive MCF-7 and T47D human breast cancer cells. E2 (1 nM) induced a 7- to 13-fold increase in cell number in both cell lines compared to untreated cells and the mitogenic potencies of 16alpha-OHE1 or 16alpha-OHE2 were comparable to or greater than E2. In contrast, 2-OHE1 and 2-OHE2 were weak mitogens in both cell lines and in cells cotreated with 1 nM E2 and 100 or 1000 nM 2-OHE1 or 2-OHE2, there was a significant inhibition of hormone-induced cell proliferation. The comparative ER agonist/antagonist activities of E2 and the metabolites on transactivation were determined in T47D cells transiently transfected with constructs containing promoter inserts from the cathepsin D (pCD) and creatine kinase B (pCKB) genes. E2, 16alpha-OHE2 and 16alpha-OHE1 induced reporter gene activity in both MCF-7 or T47D cells transfected with pCKB or pCD. In contrast, 2-OHE1 and 2-OHE2 did not exhibit ER agonist activity for these transactivation assays, but in cells cotreated with E2 plus 2-OHE1 or 2-OHE2, there was a significant decrease in the hormone-induced response. These results demonstrate that 16alpha-OHE1/16alpha-OHE2 exhibit estrogenic activities similar to that observed for E2, whereas the 2-catecholestrogens are weak ER agonists (cell proliferation) or antagonists (cell proliferation and transactivation).

Breast Neoplasms↗