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PubMed2004

Equine estrogen metabolite 4-hydroxyequilenin induces anchorage-independent growth of human mammary epithelial MCF-10A cells: differential gene expression.

Long-term exposure to synthetic and endogenous estrogens has been associated with the development of cancer in several tissues. One potential mechanism of estrogen carcinogenesis involves catechol formation and these catechols are further oxidized to electrophilic/redox active o-quinones, which have the potential to both initiate and promote the carcinogenic process. Previously we showed that 4-hydroxyequilenin (4-OHEN) autoxidized to an o-quinone and caused a variety of damage to DNA. Since these deleterious effects could contribute to gene mutations, we investigated the Chinese hamster V79 cells to ascertain the relative ability of estradiol, 4-hydroxyestradiol, 17beta-hydroxyequilenin, 4,17beta-hydroxyequilenin, estrone, 4-hydroxyestrone, equilenin, and 4-hydroxyequilenin to induce the mutation of the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene. All the 4-hydroxylated catechols induced significantly more colony formations in V79 cells as compared to the parent phenols at 100nM, suggesting that the catechol estrogen metabolites are more mutagenic towards the hprt gene than estrogens. Since 4-OHEN induced the highest mutation frequency, we examined a biomarker for transformation potential of this compound in MCF-10A cells using an anchorage-independent growth assay. Although 4-OHEN induced anchorage-independent growth of these cells, the isolated clones were not able to grow as tumors in vivo when injected into nude mice. These cells were assayed for genetic changes using cDNA microarrays. Real time RT-PCR confirmation of some of the differentially expressed genes showed down-regulation of metallothionein 2A, p53, BRCA1, and c-myc. Moreover, we showed the involvement of other genes important in cell transformation and oxidative stress, strengthening the hypothesis that this mechanism plays a considerable role in 4-OHEN-induced anchorage-independent growth.

Animals↗
PubMed2001

Selective synthesis of 4-methoxyestrogen from 4-hydroxyestrogen.

The introduction of an oxygen atom into the C-6 position of 4-hydroxyestrogen allowed for the selective methylation of the two phenolic hydroxyl groups. When the 6-oxo derivative of 4-hydroxyestrone was benzylated in ethanol, only the 3-monobenzyl ether was obtained without formation of the 4-monobenzyl ether. Moreover, the 6-carbonyl group was further reduced to methylene almost quantitatively in the reaction of 4-acetoxy-6-oxoestrone 3-benzyl ether derivative with sodium borohydride. Therefore, 4-methoxyestrogen was synthesized by essentially combining these two reactions.

Estradiol↗
PubMed1999

Behaviour and occurrence of estrogens in municipal sewage treatment plants--II. Aerobic batch experiments with activated sludge.

Aerobic batch experiments containing a diluted slurry of activated sludge from a real sewage treatment plant (STP) near Frankfurt/Main were undertaken, in order to investigate the persistence of natural estrogens and contraceptives under aerobic conditions. The batch experiments showed that while in contact with activated sludge the natural estrogen 17 beta-estradiol was oxidized to estrone, which was further eliminated in the batch experiments in an approximate linear time dependence. Further degradation products of estrone were not observed. 16 alpha-hydroxyestrone was rapidly eliminated, again without detection of further degradation products. The contraceptive 17 alpha-ethinylestradiol was principally persistent under the selected aerobic conditions, whereas mestranol was rapidly eliminated and small portions of 17 alpha-ethinylestradiol were formed by demethylation. Additionally, two glucuronides of 17 beta-estradiol (17 beta-estradiol-17-glucuronide and 17 beta-estradiol-3-glucuronide) were cleaved in contact with the diluted activated sludge solution and thus 17 beta-estradiol was released. The glucuronidase activity of the activated sludge was further confirmed by the cleavage of 4-methylumbelliferyl-beta-D-glucuronide (MUF-beta-glucuronide) in a solution of a activated sludge slurry and Milli-Q-water (1:100, v/v). The turnover rate obtained was approximately steady state, with a turnover rate of 0.1 mumol/l for the released MUF. Hence, it is very likely that the glucuronic acid moiety of 17 beta-estradiol glucuronides and other estrogen glucuronides become cleaved in a real municipal STP, so that the concentrations of the free estrogens increase.

Aerobiosis↗
PubMed1998

Synergistic induction of DNA strand breakage by catechol-estrogen and nitric oxide: implications for hormonal carcinogenesis.

Estrogen is a known risk factor for human breast cancer, although the mechanism by which estrogens induce cancer remains unestablished. We have demonstrated that DNA strand breakage is induced synergistically when pBR322 plasmid DNA is incubated in the presence of both a nitric oxide (NO)-releasing compound (diethylamine NONOate, etc.) and a catechol-estrogen (2- or 4-hydroxyestradiol or -hydroxyestrone). Either the NO-releasing compound or the catechol-estrogen alone induced much fewer strand breaks. Estradiol, estrone, O-methylated catechol-estrogens, and diethylstilbestrol did not exert such DNA damaging effects. Strand breakage induced by NO plus 2- or 4-hydroxyestradiol was inhibited by carboxy-PTIO (an NO-trapping agent) and, to a lesser extent, by superoxide dismutase. Antioxidants (e.g., N-acetylcysteine, ascorbate), but not HO. scavengers, exhibited inhibitory effects. A possible mechanism for this strand breakage would be: (1) NO mediates conversion of catechol-estrogens to quinones, (2) the quinone/hydroquinone redox system produces O2.-, and (3) O2.- reacts with NO to form peroxynitrite, which causes DNA strand breaks. Our results imply that interaction of catechol-estrogens and NO, both known to be formed in human breast and uterus, leads to production of a potent oxidant(s), which could cause damage in cells and DNA, thus playing an important role in hormonal carcinogenesis.

Antioxidants↗
PubMed1999

DNA damage induced by catecholestrogens in the presence of copper (II): generation of reactive oxygen species and enhancement by NADH.

Certain estrogen metabolites are involved in carcinogenesis and the development of resistance to methotrexate (MTX). In this study, we determined whether these well-established biological effects correlate with the relative efficiency of several estrogen metabolites to induce DNA strand breaks in the presence of copper, and investigated the potential enhancing effect of reduced nicotinamide adenine dinucleotide (NADH). DNA strand breaks induced by estradiol metabolites were measured by the conversion of supercoiled phage phiX-174 RF1 DNA to open circular and linear forms. The most active catecholestrogens were the 4-hydroxy derivatives, which produced about 2.5 times more DNA double strand breaks than the 2-hydroxy derivatives, while estradiol and 16alpha-hydroxyestrone were inactive. In addition, our results show that 4-hydroxyestradiol (4-OHE2) at physiological concentrations was capable of exhibiting DNA cleaving activity. The formation of these catecholestrogen-induced DNA strand breaks was associated with the utilization of oxygen and the generation of H2O2, because catalase inhibited the DNA cleaving activity of 4-OHE2. Interestingly, we also observed that NADH enhanced the induction of DNA strands breaks by 4-OHE2/Cu(II), probably by perpetuating the redox cycle between the quinone and the semiquinone forms of the catecholestrogen. In conclusion, this study demonstrated that the relative efficiency of 2-, and 4-hydroxyestrogen in carcinogenesis and for the enhancement of MTX resistance correlates with their relative capability to induce DNA strand breaks. In order to inhibit these estrogen-mediated biological effects, it may be important to develop different strategies to block the production of reactive oxygen species by the catecholestrogen-redox cycle.

Bacteriophage phi X 174↗
PubMed2000

Catecholestrogens excretion in smoking and non-smoking postmenopausal women receiving estrogen replacement therapy.

Estrogens are involved in the etiology of breast cancer. Their blastomogenic influence may be partly realized through their conversion into catecholestrogens, rate of which may be modified by smoking. The risk of having breast cancer diagnosed can increase in women using estrogen replacement therapy (ERT). The principal aim of this investigation was to compare the excretion of classical estrogens and catecholestrogens in smoking and non-smoking postmenopausal women receiving Progynova (estradiol valerate, 2 mg/day, 1 month). Total 16 women were studied before and after treatment. Urinary estrogen profile method based on isotope dilution capillary gas chromatography-mass spectrometry was used. Before ERT, significantly lower excretion of 16-epiestriol and 4-hydroxyestrone (4-OHE1) and lower ratio of 4-OHE1/E1 were revealed in smokers. After ERT, much higher excretion of 2-OHE1, and 4-hydroxyestradiol (4-OHE2), higher ratios of 2-OHE1/E1 and 4-OHE1/E1 and lower ratio of 2-methoxyestrone/2-OHE1 were discovered in smokers as compared to non-smoking women. In conclusion only combination of ERT + smoking and not smoking itself leads to the specific prevalence of catecholestrogens (2-OH- and carcinogenic and DNA-damaging 4-OH-metabolites) that may increase risk of genotoxic variant of hormone-induced breast carcinogenesis without influence on the total morbidity.

Breast Neoplasms↗
PubMed2001

Isolation and characterization of the monkey UDP-glucuronosyltransferase cDNA clone monUGT1A01 active on bilirubin and estrogens.

Although enzymes that catalyze the formation of steroids are well known, less information is available about the enzymes involved in the metabolism of these hormones. Steroid glucuronidation, by UDP-glucuronosyltransferase enzymes, is one mechanism by which steroid hormones can be metabolized and eliminated from a tissue. Previous results suggest that the monkey represents the most appropriate animal model for studying the physiologic relevance of steroid glucuronidating enzymes. The monkey UGT1A01 cDNA clone was isolated by RT-PCR amplification of the liver RNA. The cDNA contains an open reading frame of 1599 bp encoding a protein of 533 residues. The primary structure of monkey UGT1A01 is 95% identical to human UGT1A1. To compare monkey and human UGT1A1 enzymes, both cDNA clones were transfected into HK293 cells and stable cell lines expressing each UGT1A1 protein were established. Western blot analysis of the monUGT1A01-HK293 and hUGT1A1-HK293 cell lines using a anti-UGT1A polyclonal antibody (RC-71) revealed expression of exogenous 55 kDa UGT1 proteins. The transferase activities of monkey and human UGT1A1 proteins were tested with over 60 compounds and were demonstrated to be active on the same compounds. For endogenous compounds only bilirubin and C18 steroids were glucuronidated by these enzymes. Using microsome preparation (from HK293 cell expressing monkey UGT1A01), the apparent K(m) values were 13, 5 and 6 microM for the conjugation of estradiol, 2-hydroxyestradiol and 2-hydroxyestrone, respectively, and were very similar to the values obtained with human UGT1A1. Specific RT-PCR analysis demonstrated the expression of monkey and human UGT1A1 transcripts in several tissues including liver, kidney, intestine, prostate, testis and ovary suggesting a contribution of this isoenzyme to estrogen metabolism in the cynomolgus monkey as in human.

Amino Acid Sequence↗
PubMed2002

In vitro pro- and antioxidant properties of estrogens.

The pro- and antioxidant properties of estrogens are subject of debate. The apparent discrepancy is largely caused by the chemical heterogeneity in the estrogen family and by their concentration and the environment in which they are found. To gain some insight into this debate, we determined whether estradiol (E(2)), estrone (E(1)), the 2-, 4- and 16alpha-hydroxyestrogens and also the 2- and 4-methoxyestrogens are: (1) good electron-donors; (2) capable of O(2) consumption and DNA strand break induction; (3) capable of inhibiting lipid peroxidation in vitro. E(2), E(1) and 16alpha-hydroxyestrone (16alpha-OHE(1)) were not pro-oxidants and were rather weak antioxidants, while the 2- and 4-hydroxyestrogens demonstrated both properties inducing DNA strand breaks damage as well as inhibiting lipid peroxidation. The 4-hydroxyestrogens consumed O(2) and induced DNA strand breaks to a level approximately 2.5-fold higher than the 2-hydroxyestrogens, but these hydroxyestrogens exhibited similar antioxidant capacity, as measured by inhibition of lipid peroxidation. The 4-methoxyestrogens cannot induce oxidative damage to DNA but can inhibit lipid peroxidation, although being less potent than the 2-methoxyestrogens and the 2- and 4-hydroxyestrogens. The 2-methoxyestrogens were both potent electron donors and inhibitors of lipid peroxidation. Although 2-methoxyestrogens cannot generate superoxide in vitro, they may also be considered pro-oxidants in vivo.

Antioxidants↗
PubMed2003

Activation of matrix metalloproteinase-2 and -9 by 2- and 4-hydroxyestradiol.

Breast cancer patients frequently develop metastases. This process requires the degradation of extracellular matrix proteins which act as a barrier to tumour cell passage. These proteins can be degraded by proteases, mainly the matrix metalloproteinases (MMPs). MMP-2 and -9 which are frequently detected in breast cancer tissues. ProMMPs are released from cancer cells, and their activation is considered to be a crucial step in metastases development. In breast cancer, estrogen metabolism is altered favouring the accumulation of 2- and 4-hydroxyestradiol (2- and 4-OHE(2)). These estradiol metabolites can generate free radicals. Since reactive species are known activators of proMMPs, this study was designed to determine if the free radicals generated by 2- and 4-OHE(2) can activate proMMP-2 and -9. Activation of MMPs by hydroxyestradiol was determined by monitoring the cleavage of a fluorogenic peptide and by zymography analysis. Both estradiol metabolites activated the MMP-2 and -9. 4-OHE(2) was a more potent activator than 2-OHE(2), which reflects its higher capacity to generate free radicals. ProMMPs activation was mainly mediated through O(2)*-, although the free radical HO* also activated the proMMPs but to a lesser extent. ProMMPs activation was not observed with estrogens that cannot generate free radicals, i.e. estradiol, estrone, 2- and 4-methoxyestradiol, and 16alpha-hydroxyestrone. These results demonstrate that 2- and 4-OHE(2) at a concentration as low as 10(-8)M can activate the proMMP-2 and -9 and might play an important role in the invasion of breast cancer cells.

Copper↗
PubMed1998

Effect of estrogens on IL-1beta promoter activity.

It is well documented that steroid hormones modulate cytokine gene expression. In some tissues estrogens are known to suppress cytokine production while in other tissue types, cytokine expression is enhanced by the hormone. This study was conducted to investigate the regulatory mechanisms which underlie the modulation of the interleukin-1beta (IL-1beta) gene at the transcription level. To accomplish this, the macrophage cell line RAW264.7, which appeared insensitive to 17beta-estradiol (E2) treatment, was stably transfected with the human estrogen receptor (ER) and an IL-1beta promoter-CAT reporter construct. E2 markedly enhanced LPS-induced IL-1beta promoter-driven CAT activity in an E2 dose dependent manner. This responsiveness was estrogen specific since no synergism was observed between LPS and the sex steroids testosterone or progesterone while the estrogen analogue 17alpha-estradiol stimulated only at 10 to 100 times the amount required for 17beta-E2. Several antiestrogens, H1285, ICI 182 780, and tamoxifen inhibited the estrogen stimulated enhancement of IL-1beta promoter activity in a dose-dependent manner, indicating that this effect was indeed mediated through the ER in a ligand dependent manner. The estrogenic effect appeared to be indirect and time dependent since the addition of E2 was required hours prior to LPS stimulation; addition of E2 and LPS at the same time resulted in a greatly reduced estrogenic effect. The estrogen metabolites 17-epiestriol and 16-keto-17beta-E2 displayed an estrogenic response virtually indistinguishable from E2. 4-Hydroxyestradiol displayed activity only at 100-fold the concentration of E2 while 2-hydroxyestrone showed no activity at any of the concentrations tested. Overall the results demonstrate that E2 and some metabolites of E2 synergize with LPS to markedly enhance IL-1beta promoter activity through ER mediated processes.

Animals↗
PubMed2005

Measuring fifteen endogenous estrogens simultaneously in human urine by high-performance liquid chromatography-mass spectrometry.

A sensitive, specific, accurate, and precise high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method for measuring the absolute quantities of 15 endogenous estrogens and their metabolites in human urine has been developed and validated. The method requires a single hydrolysis/extraction/derivatization step and only 0.5 mL of urine, yet is capable of simultaneously quantifying estrone and its 2-, 4-methoxy and 2-, 4-, and 16alpha-hydroxy derivatives, and 2-hydroxyestrone-3-methyl ether; estradiol and its 2-, 4-methoxy and 2-, 16alpha-hydroxy derivatives, 16-epiestriol, 17-epiestriol, and 16-ketoestradiol in pre- and postmenopausal women as well as men. Standard curves are linear over a 10(3)-fold concentration range with the standard error of the estimate (SEE) and the relative standard error of the estimate (RSEE) for the linear regression line ranging from 0.0131 to 0.1760 and 1.2 to 7.3%, respectively. The lower limit of quantitation for each estrogen is 0.02 ng/0.5 mL urine sample (2 pg on column), with the percent recovery of a known added amount of compound (accuracy) of 96-107% and an overall precision, including the hydrolysis, extraction, and derivatization steps, of 1-5% relative standard deviation (RSD) for samples prepared concurrently and 1-12% RSD for samples prepared in separate batches. Since individual patterns of estrogen metabolism may influence the risk of breast cancer, accurate, precise, and specific measurement of endogenous estrogen metabolites in biological matrixes will facilitate future research on breast cancer prevention, screening, and treatment.

Adult↗
PubMed2005

Partition of endocrine-disrupting chemicals between colloids and dissolved phase as determined by cross-flow ultrafiltration.

Cross-flow ultrafiltration (CFUF) was developed first for the isolation of natural colloids and subsequently for determining the partition of selected endocrine-disrupting chemicals (EDCs) between river colloids and dissolved phase. In this study, a 1-kDa Millipore Pellicon 2 cartridge type CFUF system was validated using a range of molecular probes spiked in natural waters. Results show that good retention (>80%) of high molecular weight (HMW, >1 kDa) molecules and low retention of low molecular weight (LMW, <1 kDa) molecules can be achieved at high concentration factor (cf) values in sampling mode or over long time scales in recirculation mode. The interactions between aquatic colloids and EDCs were studied by mixing EDCs, water, and colloids previously isolated by CFUF for a certain duration, followed by the separation of the target compounds between the truly dissolved and colloid-bound phases by CFUF and analysis by gas chromatography-mass spectrometry (GC-MS). The kinetics of EDCs binding to colloids were relatively rapid, reaching equilibrium within 5 min. The mass balance of chosen EDCs through CFUF system was fully investigated, with good recovery for the relatively polar EDCs such as estrone and 17beta-estradiol. On the basis of EDC sorption by colloids, the partition coefficient normalized to colloidal organic carbon content (Kcoc) was 8.85 x 10(3), 1.50 x 10(4), 8.85 x 10(3), 4.87 x 10(4), and 1.59 x 10(4) mL/g for bisphenol A, estrone, 17beta-estradiol, 17alpha-ethynylestradiol, and 16alpha-hydroxyestrone, respectively, which are comparable with the values reported in the literature. In addition, it has been shown that the Kcoc values of EDCs were relatively independent of their octanol-water partition coefficient (Kow) values, suggesting the important role of different binding mechanisms other than nonspecific hydrophobic interaction between EDCs and natural colloids. As the CFUF-GC-MS method can be used to quantify very low concentration of pollutants and is not limited to fluorescent compounds, it has the potential to be a widely applicable separation/analytical tool for determining the partition of organic pollutants between colloidal materials and dissolved phase.

Adsorption↗
PubMed2001

Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage in the rat mammary tissues: formation of single-strand breaks, apurinic sites, stable adducts, and oxidized bases.

Epidemiological data strongly suggest that a woman's risk of developing breast cancer is directly related to her lifetime estrogen exposure. Estrogen replacement therapy in particular has been correlated with an increased cancer risk. Previously we showed that the equine estrogens equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are metabolized to the catechol, 4-hydroxyequilenin which autoxidizes to an o-quinone causing oxidation and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1227]. In the present study, we injected 4-hydroxyequilenin into the mammary fat pads of Sprague-Dawley rats. Analysis of cells isolated from the mammary tissue for DNA single-strand breaks and oxidized bases using the comet assay showed a dose-dependent increase in both types of lesions. In addition, LC-MS-MS analysis of extracted mammary tissue showed the formation of an alkylated depurinating guanine adduct. Finally, extraction of mammary tissue DNA, hydrolysis to deoxynucleosides, and analysis by LC-MS-MS showed the formation of stable cyclic deoxyguanosine and deoxyadenosine adducts as well as oxidized bases. This is the first report showing that 4-hydroxyequilenin is capable of causing DNA damage in vivo. In addition, the data showed that 4-hydroxyequilenin induced four different types of DNA damage that must be repaired by different mechanisms. This is in contrast to the endogenous estrogen 4-hydroxyestrone where only depurinating guanine adducts have been detected in vivo. These results suggest that 4-hydroxyequilenin has the potential to be a potent carcinogen through the formation of variety of DNA lesions in vivo.

Animals↗
PubMed2003

Spectroscopic characterization of the 4-hydroxy catechol estrogen quinones-derived GSH and N-acetylated Cys conjugates.

Estrogens, including the natural hormones estrone (E(1)) and estradiol (E(2)), are thought to be involved in tumor induction. Specifically, catechol estrogen quinones (CEQs) derived from the catechol estrogens 4-hydroxyestrone (4-OHE(1)) and 4-hydroxyestradiol (4-OHE(2)) react with DNA and form DNA adducts (Cavalieri, E. L., et al. (1997) Proc. Natl Acad. Sci. U.S.A. 94, 10037). CEQs are also conjugated with GSH, a reaction that prevents damage to DNA, providing biomarkers of exposure to CEQs. Current detection limits for these analytes by HPLC with multichannel electrochemical detection are in the picomole range (Devanesan, P., et al. (2001) Carcinogenesis 22, 489). To improve the detection limit of CEQ-derived conjugates, spectrophotometric monitoring was investigated. Fluorescence and/or phosphorescence spectra of the 4-OHE(1), 4-OHE(2), Cys, N-acetylcysteine (NAcCys), 4-OHE(1)-2-SG, and 4-OHE(2)-2-SG conjugates and their decomposition products 4-OHE(1)-2-NAcCys and 4-OHE(2)-2-NAcCys were obtained at 300 and 77 K. It is shown that (i) 4-OHE(1)- and 4-OHE(2)-derived SG and NAcCys conjugates are weakly fluorescent at 300 K (with the emission maximum at 332 nm) but strongly phosphorescent at 77 K; (ii) Cys and NAcCys exhibit fluorescence and phosphorescence only at 77 K; and (iii) 4-OHE(1) and 4-OHE(2) are weakly fluorescent at 300 and 77 K and not phosphorescent. The phosphorescence spectra of SG and NAcCys conjugates are characterized by a weak origin band at approximately 383 nm and two intense vibronic bands at 407 and 425 nm. After they are cooled from 300 to 77 K, the total luminescence intensity of SG and NAcCys conjugates increases by a factor of approximately 150 predominantly due to phosphorescence enhancement. Theoretical calculations revealed, in agreement with the experimental data, that the lowest singlet (S(1)) and triplet (T(1)) states of 4-OHE(2)-2-NAcCys are of n,pi* and pi,pi* character, respectively, leading to a large intersystem crossing yield and strong phosphorescence. The limit of detection (LOD) for CEQ-derived conjugates, based on phosphorescence measurements, is in the low femtomole range. The concentration LOD is approximately 10(-9) M. Therefore, we propose that capillary electrophoresis interfaced with low temperature phosphorescence detection can be used to test for human exposure to CEQs by analyzing urine.

Acetylcysteine↗
PubMed2000

Studies on neurosteroids. Part XIII. Characterization of catechol estrogens in rat brains using liquid chromatography-mass spectrometry-mass spectrometry.

The existence of catechol estrogens in rat brains was clarified using liquid chromatography-atmospheric pressure chemical ionization-ion trap-mass spectrometry-mass spectrometry (LC-APCI-MS2). The catechol estrogens were extracted in the presence of ascorbic acid and then derivatized to acetates with acetic anhydride and pyridine. After a successive purification with silica gel mini-column chromatography, reversed-phase solid-phase extraction and preparative HPLC, the obtained fractions containing the catechol estrogen acetates were subjected to LC-APCI-MS2. 2-Hydroxyestrone, 2-hydroxyestradiol and their 4-hydroxy isomers were identified as acetates by comparison with authentic samples based on their chromatographic behavior and mass spectral data. The derivatization to acetate was useful for the treatment of labile catechol estrogens.

Acetates↗
PubMed1988

Catechol-o-methyl transferase activity in the human term placenta.

Catechol-O-methyltransferase (COMT) characteristics and activity were studied using radioenzymatic techniques in placentas from normal and high-risk patients at term. The affinity of the catechol estrogen 20-hydroxyestrone (2OHE1), Km = 5 microM, for the enzyme was found to be at least 90-fold higher than that of the catecholamines norepinephrine, epinephrine, and dopamine (450, 490, and 850 microM, respectively). The product formed after incubation of placental cytosol with tritiated 20HE1 was identified as being exclusively (3H) 2-methoxyestrone, by use of high-performance liquid chromatography. Placental COMT activity after normal spontaneous delivery was no different from that obtained after elective cesarean section (270 +/- 20 versus 275 +/- 27, expressed as mean +/- SE activity nanomoles of 2-methoxyestrone formed per hour/mg protein). Placental COMT activity at term in women with hypertension (toxemia [T] or chronic hypertension [CHBP]) was significantly lower than in control subjects (284 +/- 27 versus 183 +/- 26; P less than 0.05). No significant differences in enzyme activity were found between T and CHBP (175 +/- 37 versus 210 +/- 32, P = NS). There were also no differences in COMT activity of diabetic classes A-R (White classification), fetal distress (with or without acidosis), and controls. The possible interference of antihypertensive drugs used by the patients in the study on COMT activity was assessed. Incubations of healthy placental cytosol with hydralazine, methyldopa, and Mg++ in their estimated plasma therapeutic concentrations had no effect on placental COMT activity. The present study suggests that placental COMT activity is low in patients with hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Agents↗
PubMed1989

The effects of cimetidine on the oxidative metabolism of estradiol.

Cimetidine, a histamine H2-receptor antagonist widely used to treat peptic ulceration, is known to cause gynecomastia and sexual dysfunction in some men. Since cimetidine inhibits the cytochrome P-450-dependent biotransformation of numerous drugs, we investigated the possibility that it might also inhibit the cytochrome P-450--dependent metabolism of estradiol. Radiometric analysis of urine and serum samples from nine normal male volunteers showed that the extent of 2-hydroxylation of estradiol was significantly reduced from a mean (+/- SEM) of 31.7 +/- 2.3 percent to 19.7 +/- 2.3 percent (P less than 0.0001) after two weeks of oral treatment with cimetidine (800 mg twice a day); the 16 alpha-hydroxylation of estradiol was unaffected. At the same time, the urinary excretion of 2-hydroxyestrone decreased by approximately 25 percent (P less than 0.0002), and the serum concentration of estradiol increased by approximately 20 percent (P less than 0.04). The mean percentage of estradiol 2-hydroxylation was also rapidly reduced, from 36.8 +/- 4.4 percent to 24.5 +/- 3.4 percent in six men after one week of oral cimetidine at a lower dosage (400 mg twice a day; P less than 0.0006). In a separate study of seven men, ranitidine, a second-generation H2-receptor antagonist, was found to have no effect on the 2-hydroxylation of estradiol. This study demonstrates that the administration of cimetidine to men decreases the 2-hydroxylation of estradiol and results in an increase in the serum estradiol concentration. This mechanism may help to account for the signs and symptoms of estrogen excess reported with the long-term use of cimetidine.

Administration, Oral↗
PubMed2005

Estrogenic effect of yam ingestion in healthy postmenopausal women.

OBJECTIVE: Yam (Dioscorea) has been used to treat menopausal symptom folklorically. This study was to investigate the effects of yam ingestion on lipids, antioxidant status, and sex hormones in postmenopausal women. METHODS: Twenty-four apparently healthy postmenopausal women were recruited to replace their staple food (rice for the most part) with 390 g of yam (Dioscorea alata) in 2 of 3 meals per day for 30 days and 22 completed the study. Fasting blood and first morning urine samples were collected before and after yam intervention for the analyses of blood lipids, sex hormones, urinary estrogen metabolites and oxidant stress biomarker. The design was a one arm, pre-post study. A similar study of postmenopausal women (n = 19) fed 240 g of sweet potato for 41 days was included as a control study. Serum levels of estrone, estradiol and SHBG were analyzed for this control group. RESULTS: After yam ingestion, there were significant increases in serum concentrations of estrone (26%), sex hormone binding globulin (SHBG) (9.5%), and near significant increase in estradiol (27%). No significant changes were observed in serum concentrations of dehydroepiandrosterone sulfate, androstenedione, testosterone, follicular stimulating hormone, and luteinizing hormone. Free androgen index estimated from the ratio of serum concentrations of total testosterone to SHBG decreased. Urinary concentrations of the genotoxic metabolite of estrogen, 16alpha-hydroxyestrone decreased significantly by 37%. Plasma cholesterol concentration decreased significantly by 5.9%. Lag time of low-density lipoprotein oxidation prolonged significantly by 5.8% and urinary isoprostane levels decreased significantly by 42%. For the control subjects fed with sweet potato, all three hormone parameters measured were not changed after intervention. CONCLUSION: Although the exact mechanism is not clear, replacing two thirds of staple food with yam for 30 days improves the status of sex hormones, lipids, and antioxidants. These effects might reduce the risk of breast cancer and cardiovascular diseases in postmenopausal women.

Aged↗