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PubMed1991

Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol.

Research studies have demonstrated a strong association between estrogen metabolism and the incidence of breast cancer, and we have therefore sought pharmacological means of favorably altering both metabolism and subsequent risk. Indole-3-carbinol (I3C), obtained from cruciferous vegetables (e.g., cabbage, broccoli, etc.), is a known inducer of oxidative P-450 metabolism in animals. We investigated the effects in humans of short-term oral exposure to this compound (6-7 mg/kg/day over 7 days). We used an in vivo radiometric test, which provided a highly specific and reproducible measure of estradiol 2-hydroxylation before and after exposure to I3C. In a group of 12 healthy volunteers, the average extent of reaction increased by approximately 50% during this short exposure (p less than 0.01), affecting men and women equally. We also measured the urinary excretion of two key estrogen metabolites, 2-hydroxyestrone (2OHE1) and estriol (E3). We found that the excretion of 2OHE1 relative to that of E3 was significantly increased by I3C, further confirming the ongoing induction of 2-hydroxylation. These results indicate that I3C predictably alters endogenous estrogen metabolism toward increased catechol estrogen production and may thereby provide a novel "dietary" means for reducing cancer risk.

Adult↗
PubMed1984

Effects of 2-hydroxyestradiol-17 beta, 2-hydroxyestradiol-17 alpha, and 4-hydroxyestrone on the preovulatory luteinizing hormone surge in the rat: agonist and antagonist actions.

Four-day cycling rats equipped with intracardiac catheters were injected with 2-hydroxyestradiol-17 beta (2OHE2-17 beta) at 0800, 0900, 1000, and 1200 h on the morning of proestrus. The administration at 0800 and 0900 h resulted in abolition of the afternoon preovulatory LH surge in virtually all animals. Injections given at 1000 and 1200 h were ineffective in this respect. The isomeric catechol estrogen 4-hydroxyestrone effectively inhibited the LH surge when given at 0900 h, but not if injected at 1000 or 1200 h. In contrast, the nonestrogenic 2-hydroxyestradiol-17 alpha was effective in blocking the LH surge when given at 0900 or 1000 h. Rats treated with 2OHE2-17 beta at 1000 h responded normally to exogenous LHRH administration in the afternoon, indicating that the action of 2OHE2-17 beta is at the hypothalamic level. 2OHE2-17 beta and 4-hydroxyestrone, which are potent estrogens, may act in this instance first as estrogen agonists, advancing the "time window" when their catechol antagonist properties in blocking the LH surge can be functional. The nonuterotropic 2-hydroxyestradiol-17 alpha and 2-hydroxyestrone act solely as catechol estrogens and inhibit the preovulatory LH surge if administered at a time when they be present during this physiological window, which is thought to involve events at the estrogen-catecholaminergic interphase.

Analysis of Variance↗
PubMedDate not supplied

4-Hydroxyestradiol is conjugated with thiols primarily at C-2: evidence from regiospecific displacement of tritium by rat liver microsomes or tyrosinase.

4-Hydroxyestradiol bearing a 3H label specifically at C-2 was prepared chemically and incubated with male rat liver microsomes or mushroom tyrosinase. A very high proportion (80-90%) of the 3H was displaced from the labeled steroid when either glutathione or N-acetylcysteine was present, and tyrosinase was shown not to require NADPH as cofactor for this reaction. In either case, only negligible amounts (less than 3%) of the 3H radioactivity were found associated with water-soluble adducts in contrast to 3H-labeled 2-hydroxyestradiol, which gave rise to about 25% of such products. The effect of ascorbic acid on the microsomal reaction with regiospecifically labeled estradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol was also investigated, and the results are discussed in terms of the reactivity at different carbon atoms in ring A of the catechol estrogens. All the evidence points to conjugation of 4-hydroxyestradiol with glutathione or N-acetylcysteine at C-2 but not C-1 of this highly reactive catechol estrogen. Measuring the displacement of 3H as 3H2O from specific positions in the steroid ring provides a useful and sensitive method to assess the formation of adducts in cases where their isolation and characterization is particularly difficult.

Animals↗
PubMed1996

Possible mechanism of induction of benign prostatic hyperplasia by estradiol and dihydrotestosterone in dogs.

A mechanism of induction of canine benign prostatic hyperplasia (BPH) by androgen-stimulated growth of prostatic cells exposed to estrogen-induced toxicity. Estrogen is thought to be activated by redox cycling of catechol metabolites, a mechanism of generation of active radicals. Mongrel dogs, 4 animals/group, were sham-operated (controls) or were treated for 60 days with implants of 5 alpha-dihydrotestosterone and/or estradiol-17 beta. The activities of drug and hormone metabolizing enzymes (aryl hydrocarbon hydroxylase, 7-ethoxycoumarin O-deethylase, and estradiol-17 beta-2- and -4-hydroxylase) in prostate were significantly elevated by chronic treatment with either estradiol-17 beta or 5 alpha-dihydrotestosterone plus estradiol-17 beta, but not in kidney or liver which are not targets of hormone-induced hyperplasia. Activities of the detoxifying enzymes catalase and glutathione peroxidase I in prostate were increased by estradiol-17 beta treatment, whereas in kidney or liver they were not affected or changed to a lesser degree than observed in prostate. Free radial-induced damage (carbonyl content) of proteins was observed in prostate of dogs treated with either estradiol-17 beta or 5 alpha-dihydrotestosterone plus estradiol-17 beta and in liver protein by treatment with either 5 alpha-dihydrotestosterone or 5 alpha-dihydrotestosterone plus estradiol-17 beta. It was concluded that the patterns of estradiol-17 beta- or 5 alpha-dihydrotestosterone plus estradiol-17 beta-induced increases in activities of catechol estrogen synthase and of other drug metabolizing enzymes were consistent with the postulated free radical generation by redox cycling of catechol estrogen specifically in the prostate. The increases in activities of detoxifying enzymes may represent an (albeit insufficient) response to prostatic free radical damage to protein in prostate is consistent with a postulated induction of BPH via injury by estrogen metabolites followed by 5 alpha-dihydrotestosterone-stimulated growth of altered prostatic cells.

7-Alkoxycoumarin O-Dealkylase↗
PubMed2004

Polymorphism of estrogen metabolism genes and cataract.

Cataract is the leading cause of visual impairment in older adults in the world. Age-related lens opacities are common and are frequent causes of loss of vision. The incidence of cataract increases significantly with increasing age in women only. The onset coincides with estrogen deficiency that occurs after menopause. Hormone replacement therapy has proven beneficial to selected postmenopausal women. Estrogen effects on biological system are modulated via the estrogen receptors (ER) and/or estrogen metabolites. Although ER have been detected in ocular tissue, whether ER polymorphism is related to cataract is not known at present. The polymorphisms of estrogen metabolizing enzymes are also related to the serum concentration and activity of estrogen. Polymorphism such as cytochrome P450c17 (A2/A2), cytochrome P450c1A (vt/vt) will result in increased formation of catechol estrogen, while people with catechol-O-methyltransferase (COMT) polymorphism COMT (L/L) will have decreased metabolism of catechol estrogen and decreased level of methoxyestradiol. COMT was also involved in tamoxifen metabolism which may further decrease the activity of COMT in breast cancer patients treated with tamoxifen. It is known that a 4-7% increase in cataract was found in tamoxifen-treated breast cancer patients than non-user. The 7.0% COMT (L/L) genotype in general population corresponded well with the 4-7% of cataract formation in tamoxifen-treated breast cancer patients. Our hypothesis is that breast cancer patients with COMT (L/L) genotype may be at increased risk of cataract formation after tamoxifen treatment.

Biomarkers, Tumor↗
PubMed2005

Estrogen bioactivation, genetic polymorphisms, and ovarian cancer.

Recent experimental evidence has shown that catechol estrogens can be activated through metabolism to form depurinating DNA adducts and thereby initiate cancer. Limited data are available regarding this pathway in epithelial ovarian cancer. We conducted a case-control study of 503 incident epithelial ovarian cancer cases at the Mayo Clinic in Rochester, MN, and Jacksonville, FL, and a 48-county region in North Carolina. Six hundred nine cancer-free controls were frequency matched to the cases on age, race, and residence. After an interview to obtain data on risk factors, a sample of blood was collected for DNA isolation. Subjects were genotyped for seven common single nucleotide polymorphisms in four genes involved in catechol estrogen formation (CYP1A1 and CYP1B1) or conjugation (COMT and SULT1A1). Data were analyzed using logistic regression, stratified by race, and with adjustment for design factors and potential confounders. None of the individual genotypes were significantly associated with ovarian cancer risk. However, an oligogenic model that considered the joint effects of the four candidate genes provided evidence for an association between combinations of these genes and ovarian cancer status (P = 0.015). Although preliminary, this study provides some support for the hypothesis that low-penetrance susceptibility alleles may influence risk of epithelial ovarian cancer.

Adult↗
PubMed1992

Effects of Ponderosa pine needle ingestion of uterine vascular function in late-gestation beef cows.

Consumption of Ponderosa pine (Pinus ponderosa) needles (PN) by beef cows during late gestation results in premature delivery in association with profound constriction of the caruncular arterial bed. Further, PN extracts and plasma from PN-fed cows increase uterine arterial tone in vitro. Uterine arterial tone is a measure of the arterial resistance to stretch and controls the baseline rate of flow through the vascular bed. Uterine arterial tone results from the uptake of extracellular Ca2+ into smooth muscle cells through specific membrane channels called potential sensitive channels. Functional potential sensitive channels remain open for prolonged periods after activation, allowing a continuous uptake of Ca2+ and the maintenance of uterine arterial tone. Recent evidence from our laboratory has demonstrated that a group of estrogen metabolites produced by the placenta and(or) endometrium, called catechol estrogens, inhibits Ca2+ uptake through the potential sensitive channels. During gestation, progressive decreases in uterine arterial tone are observed, with resultant increases in uterine arterial blood flow. Thus, the continuous production of catechol estrogens may be necessary to maintain the pronounced uterine vasodilation that is required for fetal survival. Ponderosa pine needle extracts exhibit antiestrogenic activity, as evidenced by their inhibition of estrogen-induced uterine hyperemia. Data from our laboratory show that after consumption of PN by beef cows during late gestation, uterine arterial blood flow progressively decreased to less than 50% of prefeeding rates before premature delivery of a live calf.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Control of blood flow to the gravid uterus of domestic livestock species.

Uterine blood flow during pregnancy is controlled by two distinct phenomena: phasic contractility and tone. Phasic contractility, which mediates short-term contractions, functions through catecholamine activation of alpha 1-adrenergic receptors (AR), leading to hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). The phasic contractions proceed as IP3 stimulates the release of intracellular calcium stores that activate the calmodulin pathway, causing myosin filaments to slide past actin filaments; however, the contraction is quickly terminated via a reduction in free cytosolic calcium. A tonic contraction is initiated when the DAG generated during PIP2 hydrolysis binds to and activates protein kinase C (PKC) in the presence of increased cytosolic calcium, leading to shortening of the actin filaments. Concomitantly, stimulation of alpha 2-AR increases extracellular calcium uptake via the potential-sensitive channels (PSC), which potentiates activity of the membrane-bound PKC-DAG complexes, thus maintaining the degree of tonic contractility. Progesterone maintains the phasic contractility of uterine arterial smooth muscle throughout pregnancy by increasing alpha 1-AR numbers. Estrogens decrease uterine arterial tone (i.e., increase arterial diameter and flow) via their conversion to catechol estrogens by peroxidase in uterine lymphatic fluid. Catechol estrogens directly inhibit calcium uptake through PSC, resulting in a reduced activity of membrane-bound PKC-DAG complexes.

Animals↗
PubMed2001

Keratinocyte growth factor is up-regulated by estrogen in the porcine uterine endometrium and functions in trophectoderm cell proliferation and differentiation.

Keratinocyte growth factor (KGF) is expressed by uterine endometrial epithelial cells during the estrous cycle and during pregnancy in pigs, whereas KGF receptor is expressed in conceptus trophectoderm and endometrial epithelia. In particular, KGF expression in the endometrium is highest on day 12 of pregnancy. This corresponds to the period of maternal recognition of pregnancy in pigs, which is signaled by large amounts of estrogen secreted by conceptus trophectoderm acting on the endometrium. Our hypothesis is that estrogens of conceptus origin stimulate endometrial epithelial KGF expression, and, in turn, secreted KGF stimulates proliferation and differentiation of conceptus trophectoderm. To determine the factors affecting KGF expression in the uterus, endometrial explants from gilts on day 9 of the estrous cycle were cultured in the presence of 17beta-estradiol, catechol estrogens, or progesterone. 17beta-Estradiol stimulated the expression of KGF (P < 0.05), whereas catechol estrogens had no effect (P > 0.05). Between days 9 and 15 of pregnancy, proliferating cell nuclear antigen was abundant in conceptuses, but was barely detectable in uterine endometrial epithelia. To determine the effects of KGF on conceptus trophectoderm, porcine trophectoderm (pTr) cells were treated with recombinant rat KGF (rKGF). rKGF increased the proliferation of pTr cells (P < 0.01) as measured by [(3)H]thymidine incorporation. rKGF elicited phosphorylation of KGF receptor and activated the mitogen-activated protein kinase (ERK1/2) cascade in pTr cells. pTr cell differentiation was affected by rKGF, because it increased expression of urokinase-type plasminogen activator, a marker for differentiation in pTr cells. Collectively, these results indicate that estrogen, the pregnancy recognition signal from the conceptus in pigs, increases uterine epithelial KGF expression, and, in turn, KGF stimulates the proliferation and differentiation of conceptus trophectoderm.

Animals↗
PubMed1987

The multicomponent analysis of estrogens in urine by ion exchange chromatography and GC-MS--II. Fractionation and quantitation of the main groups of estrogen conjugates.

A method for the metabolic profiling of estrogen conjugates in urine is described. It mainly involves protection of carbonyl functions by ethoximation, solid extraction on Sep-Pak C18 cartridges, a number of ion exchange chromatographic steps and quantitation by capillary GC or GC-MS. The acetate form of DEAE-Sephadex is used to initially separate estrogen conjugates into four groups; unconjugated, monoglucuronides, monosulfates and double conjugates. Monoglucuronides are further subfractionated to A- and D-ring glucuronides by carbodiimide methylation of the carboxylic functions and chromatography on the free base form of DEAE-Sephadex. Double conjugates are subfractionated to disulfates and sulfoglucuronides by solvolysis and chromatography on the acetate form of DEAE-Sephadex. After the appropriate enzymatic hydrolysis or solvolysis procedures the liberated free estrogens are purified and fractionated by a series of anion exchange chromatographic steps. Finally, following trimethylsilyl ether derivatization estrogens are analysed by capillary GC or GC-MS. The method permits the quantitation of the main conjugates of all the important estrogen metabolites including catechol estrogens. The method is precise, the sensitivity depending on the quantitation mode employed GC or SIM GC-MS. The method was applied to seven late pregnancy urines the values of which are presented.

Chromatography, Ion Exchange↗
PubMed1987

Increased self-administration of cocaine following haloperidol: effect of ovariectomy, estrogen replacement, and estrous cycle.

Rats which have been trained to self-administer cocaine intravenously show a dose-dependent increase in drug intake when pretreated with dopamine antagonists. This neuroleptic-induced increase in cocaine intake may be related to the antipsychotic potency and suggests that self-administration behavior may provide a useful model for evaluating neuroleptic activity. The present study examines the influence of ovarian hormones on the potency of the neuroleptic haloperidol using the cocaine self-administration model. It was found that the potency of haloperidol fluctuated across the estrous cycle with subjects in diestrus self-administering more cocaine than animals tested in estrus or proestrus. It was also demonstrated that the potency of haloperidol was reduced significantly following ovariectomy (OVX), however this OVX-induced attenuation could not be reversed with a number of estrogen or catechol-estrogen treatments. To the extent that the self-administration model can reflect the potency of antipsychotic drugs, these data indicate that ovarian function can affect neuroleptic activity, although the hormone(s) involved remain unclear. The clinical implications of these data underscore the need to further examine the influence of female sex hormones on the therapeutic efficacy of antipsychotic drugs.

Animals↗
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↗
PubMed2003

Estrogens and organochlorine xenoestrogens and breast cancer risk.

Breast cancer is responsible for considerable morbidity and the majority of female deaths in industrialized countries. In the etiology of breast cancer many endogenous and exogenous risk factors have been discussed. It is estimated that about 40% of all cancers in women are hormonally mediated. Both estrogens and androgens play critical roles in the development of breast cancer, which has been confirmed by numerous epidemiologic data on the levels of serum and urine hormons in populations at low and high risk, as well as by case-control and cohort studies. Estrogen carcinogenesis is attributed to receptor-mediated growth and proliferation of breast epithelial cells and to DNA impairment caused by activated estrogen metabolites, e.g., catechol estrogens and free radicals. In the last decade, the organochlorine chemicals, which include pesticides, polychlorinated biphenyl congeners and other representatives of the dioxin family, have been regarded as xenoestrogens. These chemicals are capable of modulating hormonally regulated processes and inducing changes in growth factors that may be responsible for carcinogenic effect. Many case-control studies have shown the distinct association between breast adipose tissue concentrations of several organochlorine xenoestrogens and breast cancer risk. Also in some studies, the women with breast cancer had higher organochlorine levels in serum as compared with controls.

Adipose Tissue↗
PubMed2004

4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor A through phosphatidylinositol 3-kinase/Akt/FRAP pathway in OVCAR-3 and A2780-CP70 human ovarian carcinoma cells.

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1alpha and HIF-1beta subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. HIF-1 activates downstream target genes such as vascular endothelial growth factor A (VEGF-A), which plays an important role in tumor progression and angiogenesis. Estrogen exposure is considered to be the major risk factor for ovarian cancer. Estradiol (E2) is usually metabolized by CYP1A1/1A2 and CYP3A4 to the 2-hydroxy estradiol (2-OHE2) and 4-hydroxy estradiol (4-OHE2) in human liver. Many reports have suggested that the formation of 4-OHE2 is important for mammary carcinogenesis. However, the formation of 2-OHE2 may play an important role in exhibiting anticarcinogenic effects. In the present study, we have demonstrated that one of the catechol estrogen metabolites of E2, 4-OHE2, induces HIF-1alpha and VEGF-A expression at protein level in two human ovarian cancer cell lines, OVCAR-3 and A2780-CP70 cells, in dose- and time-dependent manners, whereas the other catechol estrogen metabolite of E2, 2-OHE2, does not alter HIF-1alpha and VEGF-A expression. To explore the mechanism of 4-OHE2-induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase (MAPK) signaling pathways are involved in 4-OHE2-induced HIF-1alpha and VEGF-A expression. Our findings indicate that PI3K inhibitors, LY294002 and wortmannin, inhibited HIF-1alpha and VEGF-A expression, whereas MAPK inhibitor, PD98059, did not alter HIF-1alpha and VEGF-A expression induced by 4-OHE2. 4-OHE2, but not 2-OHE2, also induced Akt phosphorylation at Ser473 in dose- and time-dependent manners, and LY294002 and wortmannin inhibited Akt phosphorylation at Ser473 induced by 4-OHE2. Our results also indicated that the mTOR/FRAP inhibitor, rapamycin, inhibited 4-OHE2-induced HIF-1alpha and VEGF-A expression. These results suggest that the PI3K/Akt/FRAP signaling pathway is required for HIF-1alpha and VEGF-A expression induced by 4-OHE2, whereas the MAPK pathway is not required. The finding that induction of HIF-1alpha and VEGF-A expression occurs via the activation of the PI3K/Akt/FRAP signaling pathway could be an important mechanism of 4-OHE2-induced carcinogenesis.

Cell Line, Tumor↗
PubMed1984

The catalytic effect of tyrosinase upon oxidation of 2-hydroxyestradiol in presence of catechol.

The hydroxylating activity of mushroom tyrosinase has been utilized for over a decade in the preparation of 2-hydroxyestradiol from estradiol, yet this same enzyme is known to function as an oxidant of o-dihydric compounds to the corresponding o-quinones. It was questioned why catechol estrogens do not react further, particularly since the tyrosinase activity (hydroxylating) is exceeded many fold by the diphenol oxidase activity of the enzyme. This report describes that the catechol estrogen will react in presence of enzyme but only if catechol is also present. Diphenol oxidase activity was measured either by the polarographic oxygen-utilization technique or by changes in the absorption spectrum at 206 and 256 nm. The enzyme activity was standardized with catechol (Km = 5.2 X 10(-4) M). The steroid did not react with the enzyme if catechol was absent. With catechol, the steroid reacted rapidly and completely (Km = 4.2 X 10(-4) M). The consumption of oxygen with catechol and 2-hydroxyestradiol was additive and stoichiometric, 1 g-atom oxygen/mol of either substrate. Kinetic analysis shows that catechol functions as an activator of the tyrosinase.

Basidiomycota↗
PubMed1998

Effects of estrogen agonists on amphetamine-stimulated striatal dopamine release.

Based upon the observation that estrogen acts in the striatum to rapidly modulate dopamine (DA) neural transmission and DA-mediated behaviors, it has been postulated that these effects of estrogen are mediated by a specific, membrane-bound receptor mechanism. To further characterize the pharmacological specificity of the estrogen binding site, the present experiments examine effects of various estrogen agonists on amphetamine (AMPH)-induced DA release from striatal tissue of ovariectomized female rats, using a superfusion method. Catechol estrogens 4-, and 2-hydroxyestradiol, but not 2-methoxyestradiol, significantly enhance AMPH-induced striatal DA release. Estrogen metabolites, estrone and estriol, and the non-steroidal estrogen analog, diethylstilbestrol, are without effects. Estradiol conjugated to bovine serum albumin (BSA) mimics the effect of estradiol to enhance stimulated striatal DA release. These results indicate that the steroidal configuration and hydroxylation on the A-ring of estrogenic compounds may be important determinants of ligand binding to the putative estrogen binding site in the striatum. Furthermore, the effectiveness of the estradiol conjugated to BSA reinforces the idea of an external membrane-bound receptor binding site in the striatum.

Amphetamine↗