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PubMed2000

Use of a combined human liver microsome-estrogen receptor binding assay to assess potential estrogen modulating activity of PCB metabolites.

Polychlorinated biphenyls (PCBs) are metabolized by hydroxylation; some of these hydroxylated metabolites exhibit estrogen-like activity in animal models. Because PCBs may have effects on human health, it is of interest to determine if human tissues also metabolize PCBs to potentially estrogenic metabolites. In this study metabolites of seven PCBs with different degrees and positions of chlorination, generated by human liver microsomal reaction mixtures (MRM) have been examined, and their affinity for human recombinant estrogen receptor-alpha (ER) has been tested before and after HPLC fractionation. Two of the three MRMs with di-chloro-biphenyls (BPs, 2,5BP and 3,4BP), one of the three MRMs with tetra-BPs (2,6,2',6'BP), and one hexa-BP (2,4,6,2',4',6'BP) generated metabolites that competed for ER. HPLC of the ER-binding MRMs generated fractions that also exhibited ER-binding. This study shows the usefulness of combining in vitro metabolism and an ER-binding assay in initial identification of PCBs with estrogen-modulating potential.

Acetates↗
PubMed2006

Interplay between estrogen-related receptor alpha (ERRalpha) and gamma (ERRgamma) on the regulation of ERRalpha gene expression.

Estrogen-related receptor alpha (ERRalpha) modulates estrogen receptor (ER)-mediated activity and is participating in the energy homeostasis by regulation of downstream target genes. The ERRalpha gene itself is proposed to be regulated by peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) through an autoregulatory loop under physiological stimulation. We have previously shown that the close family member ERRgamma is a positive regulator of ERRalpha gene expression. ERRalpha and ERRgamma are coexpressed in metabolically active tissues such as heart, kidney and muscle, yet the physiological role of ERRgamma and its relationship with ERRalpha in gene regulation are currently unknown. The present study examined the interplay of ERRgamma and ERRalpha in regulation of ERRalpha gene expression. Using real-time PCR analyses we found that ERRgamma, like the ERRalpha and PGC-1alpha is induced in mouse liver during fasting. Overexpression of ERRgamma in the HEC-1B cells robustly stimulated the multi-hormone response element (MHRE) of the ERRalpha gene promoter and this activity was repressed by increasing expression of ERRalpha. The two ERRs bind MHRE simultaneously in electrophoretic mobility shift assay (EMSA) and they were detected as multimeric complexes in cells by coimmunoprecipitation. Although ERRalpha and ERRgamma share high sequence identity, they differ in biochemical and molecular characteristics as examined by trypsin digestion, reporter activation and coactivator interaction and utilization. Using chromatin immunoprecipitation (ChIP) assay, we showed that ectopic expression of both ERRalpha and ERRgamma modifies chromatin structure at the MHRE region while ectopic expression of PGC-1alpha in HEC-1B cells promotes ERRgamma but not ERRalpha occupancy at the MHRE region of the ERRalpha gene promoter and enhances the recruitment of coactivator SRC1. These data suggested that ERRalpha and ERRgamma regulate ERRalpha gene expression with different molecular mechanisms.

Animals↗
PubMed2004

Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition.

Tamoxifen is a selective estrogen receptor modulator used in estrogen receptor-positive breast cancer. Tamoxifen is metabolized to an extremely potent antiestrogen by cytochrome P450 (CYP) 2D6, 2C9, and 3A isoforms. The selective serotonin reuptake inhibitors (SSRIs) are potent inhibitors of these CYPs. Since the prevalence of depression in breast cancer patients is nearly triple that of the general population, it is likely that a subgroup of breast cancer patients will receive long-term treatment with both an SSRI and tamoxifen. A case control design was used to investigate the possibility that a resultant decrease in production of the 4-hydroxy metabolite from chronic inhibition results in the attenuation of the antitumor effect of tamoxifen. Twenty-eight patients without recurrences of breast cancer (controls) were matched to an equal number of cases (recurrences) by cancer stage and year of diagnosis. Data were analyzed on all chronic medication exposure (> 3 months) in both cases and controls classified as to their status as CYP 2D6, 2C9, and 3A inhibitors, substrates, or inducers. No significant difference was found for CYP inhibitor or substrate exposure between cases and controls. Indeed, controls showed a slightly greater exposure to inhibitors of the relevant CYP isoforms compared to cases. These results suggested a trend toward the null hypothesis. It is unlikely that the effect of chronic exposure to potent CYP isoform inhibitors affects the antitumor effect of tamoxifen and its 4-hydroxy metabolite, supporting the safety of the continued practice of concomitant SSRI administration to breast cancer patients with depression.

Antidepressive Agents, Second-Generation↗
PubMed2005

Tamoxifen up-regulates catalase production, inhibits vessel wall neutrophil infiltration, and attenuates development of experimental abdominal aortic aneurysms.

BACKGROUND: Selective estrogen receptor modulators (SERMs), similar to estrogens, possess vasoprotective effects by reducing release of reactive oxygen species. Little is known about the potential effects of SERMs on the pathogenesis of abdominal aortic aneurysms (AAAs). This study's objective was to investigate the growth of experimental AAAs in the setting of the SERM tamoxifen. METHODS: In the first set of experiments, adult male rats underwent subcutaneous tamoxifen pellet (delivering 10 mg/kg/day) implantation (n = 14) or sham operation (n = 16). Seven days later, all animals underwent pancreatic elastase perfusion of the abdominal aorta. Aortic diameters were determined at that time, and aortas were harvested 7 and 14 days after elastase perfusion for immunohistochemistry, real-time polymerase chain reaction, Western blot analysis, and zymography. In the second set of experiments, a direct irreversible catalase inhibitor, 3-amino-1,2,4-triazole (AT), was administered intraperitoneally (1 mg/kg) daily to tamoxifen-treated (n = 6) and control rats (n = 6), starting on day 7 after elastase perfusion. Aortic diameters were measured on day 14. In a third set of experiments, rats were perfused with catalase (150 mg/kg) after the elastase (n = 5), followed by daily intravenous injections of catalase (150 mg/kg/day) administered for 10 days. A control group of rats (n = 7) received 0.9% NaCl instead of catalase. RESULTS: Mean AAA diameters were approximately 50% smaller in tamoxifen-treated rats compared with sham rats 14 days after elastase perfusion (P = .002). The tamoxifen-treated group's aortas had a five-fold increase in catalase mRNA expression (P = .02) on day 7 and an eight-fold increase in catalase protein on day 14 (P = .04). Matrix metalloprotroteinase-9 activity was 2.4-fold higher (P = .01) on day 7 in the aortas of the controls compared to the tamoxifen-treated group's aortas. Tamoxifen-treated rats had approximately 40% fewer aortic polymorphonuclear neutrophils compared to controls on day 7 (P = .05). Administration of the direct catalase inhibitor AT to tamoxifen-treated rats partially reversed the aneurysm inhibitory effect of tamoxifen by nearly 30% (P = .02). In contrast, catalase administration inhibited AAA formation by 44% (P = .002). CONCLUSIONS: The selective estrogen receptor modulator tamoxifen inhibits the development of AAAs in male rats in association with an up-regulation of catalase and inhibition of aortic wall neutrophil infiltration.

Amitrole↗
PubMed2004

Coregulator function: a key to understanding tissue specificity of selective receptor modulators.

Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and corepressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily.

Animals↗
PubMed2002

Pros and cons of existing treatment modalities in osteoporosis: a comparison between tibolone, SERMs and estrogen (+/-progestogen) treatments.

Tibolone, selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene, and estrogen (+/-progestogen) treatments prevent bone loss in postmenopausal women. They exert their effects on bone via the estrogen receptor (ER) and the increase in bone mass is due to resorption inhibition. The effect of SERMs on bone mineral density is less than that with the other treatments, but the SERM raloxifene still has a positive effect on vertebral fractures. In contrast to tibolone and estrogens (+/-progestogen), SERMs do not treat climacteric complaints, whilst estrogen plus progestogen treatments cause a high incidence of bleeding. Estrogen plus progestogen combinations have compromising effects on the breast. Tibolone and SERMs do not stimulate the breast or endometrium. Unlike SERMs, tibolone does not possess antagonistic biological effects via the ER in these tissues. Estrogenic stimulation in these tissues is prevented by local metabolism and inhibition of steroid metabolizing enzymes by tibolone and its metabolites. SERMs and estrogen (+/-progestogen) treatments increase the risk of venous thromboembolism (VTE), whilst estrogen (+/-progestogen) combinations have unwanted effects on cardiovascular events. So far, no detrimental effects of tibolone have been observed with respect to VTE or cardiovascular events. The clinical profile of tibolone therefore has advantages over those of other treatment modalities. It is also clear that tibolone is a unique compound with a specific mode of action and that it belongs to a separate class of compounds that can best be described as selective, tissue estrogenic activity regulators (STEARs).

Bone and Bones↗
PubMed2003

Identification of estrogen receptor beta expression in Chinese hamster ovary (CHO) cells and comparison of estrogen-responsive gene transcription in cells adapted to serum-free media.

Most cultured cell lines require addition of serum to the medium to maintain their proliferative capacity. For studies examining the cellular effects of estrogens serum is charcoal-stripped to remove steroids. Nonetheless, addition of the selective estrogen receptor modulator (SERM) 4-hydroxytamoxifen (4-OHT) inhibits the basal transcriptional activity of estrogen receptors alpha or beta (ERalpha or ERbeta) in transfected cells. We tested the hypothesis that elimination of serum from the culture medium will block 4-OHT's repression of basal activity. Chinese hamster ovary (CHO-K1) cells adapted to serum-free medium exhibited estrogen responsiveness that was identical with that of the cells grown in serum-containing media. 4-OHT-suppressed basal transcription of an estrogen response element (ERE)-reporter in ERalpha-transfected cells even in the absence of serum, indicating that the 4-OHT suppressive activity is not mediated by blocking ER interaction with serum estrogens. We speculate that 4-OHT-ER recruits co-repressors to suppress basal transcription. We discovered that CHO-K1 cells express ERalpha and ERbeta mRNA. However only ERbeta protein was expressed and use of ERbeta-selective 2,3-bis(4-hydroxy-phenyl)propionitrile (DPN) and ERalpha-selective 4-propyl-1,3,5-tris(4-hydroxy-phenyl)pyrazole) (PPT) revealed that only ERbeta was transcriptionally active. In conclusion, growing CHO-K1 in serum-free medium does not impact the estrogen responsiveness and this cell line expresses functional ERbeta.

Animals↗
PubMed2004

Estrogen and tamoxifen modulate cerebrovascular tone in ovariectomized female rats.

Postmenopausal estrogen deficiency increases the incidence of cerebrovascular disease. However, hormone replacement therapy is associated with an increased cardiovascular risk. Tamoxifen is a selective estrogen receptor modulator with estrogenic effects on cardiovascular risk factors, but its long-term impacts on cerebral vasculature are unknown. We hypothesized that chronic 17beta-estradiol or tamoxifen treatment exerted similar effects in reducing cerebrovascular tension in ovariectomized rats. We therefore determine whether (1) chronic 17beta-estradiol treatment could influence vasomotor activities, (2) chronic tamoxifen therapy could exert an estrogen-like or estrogen-antagonistic effect, and (3) acute exposure to estrogen could mimic the effect of 17beta-estradiol. Isometric tension was measured in cerebral arteries from female rat groups: control, ovariectomy, ovariectomy plus 17beta-estradiol treatment, ovariectomy plus tamoxifen treatment, and ovariectomized rats treated with tamoxifen and 17beta-estradiol. Ovariectomy enhanced cerebrovascular contractions to endothelin-1 or CaCl2, but not to U46619 or phenylephrine. 17beta-Estradiol therapy reversed these effects. Chronic tamoxifen treatment exerted estrogen-like actions by reversing ovariectomy-induced enhancement of vessel tone without antagonizing the effect of chronic 17beta-estradiol treatment. Ovariectomy enhanced the relaxing potency of nicardipine, and 17beta-estradiol treatment prevented this effect. Acute exposure to 10(-9) mol/L 17beta-estradiol or 10(-8) mol/L tamoxifen did not modulate contractions in rings from nonoperated female rats. In conclusion, ovariectomy differentially enhances agonist-induced cerebrovascular tone, an effect that was reversed by estrogen therapy. Tamoxifen does not act as an estrogen antagonist; instead, it functions as an estrogen agonist during estrogen deficiency. Thus, tamoxifen may confer beneficial effects similar to estrogen in cerebrovascular vessels.

Animals↗
PubMed2004

Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats.

Obesity, from declining estrogen levels after menopause, increases the risk of heart disease, diabetes, and hypertension. Ovariectomy (OVX) in rats is a good model of estrogen insufficiency. The ensuing mild obesity is useful to study how hypoestrogenism alters adiposity. This study examines the hypothesis that in ovariectomized (OVX) rats modification of estrogen levels or treatment with a selective estrogen receptor modulator, raloxifene (RAL), alters leptinemia and modulates leptin receptor (Ob-R) abundance in hypothalamus and white adipose tissue, similar to the modification of adipose status induced by hypoestrogenism. Mid- and long-term studies (7 and 22 wk) were conducted to monitor the change in leptinemia in rats after estrogen loss by OVX and after estrogen replacement by 17beta-estradiol (OVX+E(2)) or RAL treatment (OVX+RAL). Leptin was significantly higher in OVX rats vs. controls, in a time-dependent manner. This effect was reversed by both E(2) and RAL treatment at 7 wk (P < 0.05) and 22 wk (P < 0.001). Moreover, E(2) or RAL treatment reversed the OVX-induced increases in food intake, body weight, and fat mass content; the modifications of serum parameters were examined to evaluate the different lipid profiles. We also evaluated Ob-R expression in hypothalamus and adipose tissue by Western blot analysis. The expression of the long functional isoform (Ob-Rb) increased at 7 wk only in adipose tissue and decreased at 22 wk in OVX rats in both tissues; these effects were reversed by E(2) or RAL treatment. We provide evidence that central and peripheral Ob-Rb expression is related to modification of estrogen levels.

Adaptation, Physiological↗
PubMed2003

CNS: sex steroids and SERMs.

The central nervous system (CNS) is one of the main target tissues for sex steroid hormones, which act both through genomic mechanisms, modulating synthesis, release, and metabolism of many neuropeptides and neurotransmitters, and through nongenomic mechanisms, influencing electrical excitability, synaptic function, and morphological features. The identification of the brain as a de novo source of neurosteroids modulating cerebral function, suggests that the modifications in mood and cognitive performances occurring in postmenopausal women could also be related to a modification in the levels of neurosteroids, particularly allopregnanolone and DHEA, GABA-A agonist, and antagonist, respectively. The selective estrogen receptor modulators (SERMs) are compounds that activate the estrogen receptors with different estrogenic and antiestrogenic tissue-specific effects. In addition to the effects of the classic steroid hormones on the CNS, the study of selective estrogen receptor modulators impact on the neuroendocrine system has recently provided encouraging results, indicating that raloxifene analog LY 117018 and the new generation SERM EM-652 have an estrogen-like action on beta-endorphin and on allopregnanolone in ovariectomized rats, while they exert an anti-estrogenic effect in fertile rats and in ovariectomized rats treated with estrogens. In addition, raloxifene administration in postmenopausal women plays an estrogen-like effect on circulating beta-EP and allopregnanolone levels, and it restores the response of beta-EP and allopregnanolone to neuroendocrine tests. In conclusion, the positive effects of HRT on mood and cognition in postmenopausal women occur via the modulation of neuroendocrine pathways and probably also of neurosteroidogenesis. The effects of raloxifene on mood and cognition encourage the efforts in the research of an ideal estrogen replacement therapy, showing all the positive effects of estrogens and fewer side effects.

Aged↗
PubMed2007

Modulation by phenylacetate of early estrogen-mediated events in MCF-7 breast cancer cells.

PURPOSE: Phenylacetate (PA) and its derivatives constitute a group of small aromatic fatty acids that have been of considerable interest due to their anticancer properties in a number of experimental systems. We previously showed that PA can inhibit the growth of estrogen receptor (ER)+ breast cancer cells and that this activity is, at least in part, mediated by the ability of the compound to inhibit transcriptional activation driven by estrogen response elements (EREs). We now shed additional light on the antiestrogenic action of PA by determining its effects on early events in the estrogen-signaling pathway. METHODS: MCF-7 breast cancer cells were used in this study. ER-ERE binding activity, and subsequent effects on ER and progesterone receptors (PR), c-myc, and the cyclin-dependent kinase inhibitor p21ASF1/CP1/MDA-6 (p21) were evaluated using electrophoretic mobility shift assays, real-time RT-PCR, and western blotting methodologies. Effects of PA on p21 promoter activity were assessed in transient transfection experiments utilizing p21 promoter-reporter gene constructs. RESULTS: We demonstrate that PA treatment can block ER-ERE binding activity and that this effect is accompanied by downregulation of PR and c-myc, two genes which are transcriptionally regulated by estrogen through novel-ER-binding sites. Suppression of c-myc by PA is followed by increased mRNA levels of p21, an effect that is mediated by PA activation of the p21 promoter. Forced overexpression of c-myc through co-transfection of MCF-7 cells with a c-myc expression plasmid prevented PA upregulation of p21 promoter activity. CONCLUSIONS: These findings confirm the potent antiestrogenic properties of PA, indicate that its effects are mediated by inhibiting ER-ERE interactions, and suggest that downregulation of c-myc is an early event leading to increased p21 expression and cell growth inhibition.

Antimetabolites, Antineoplastic↗
PubMed2001

Hormone replacement therapy and fractures in older adults.

Estrogen deficiency in women is associated with accelerated bone loss, and estrogen replacement therapy has been proven to be effective in preventing osteoporosis and fractures in postmenopausal women. The introduction of selective estrogen receptor modulators that have an estrogen-like effect on the skeleton but have a different pattern of effects on other tissues may have an important role in the management of osteoporosis in women in the near future. In men, androgen deficiency has been shown to be associated with osteoporosis. Although androgen replacement in hypogonadal men may decrease bone resorption and increase bone mass, long-term placebo-controlled trials are needed to better define the benefits and risks of such therapy before it can be recommended. Sex hormone deficiency is linked to the development of osteoporosis in both women and men. In women, hormonal replacement by estrogen or the newly developed selective estrogen receptor modulators may prevent the development of osteoporosis and its related fractures. In men, there is early evidence that testosterone replacement therapy may enhance bone mass in hypogonadal men.

Age Distribution↗
PubMed2006

Endocrine disruptors in the marine environment: mechanisms of toxicity and their influence on reproductive processes in fish.

Recent research demonstrated how endocrine-disrupting chemicals (EDCs) may disturb wildlife populations and possibly also represent a human health risk. Much of the focus has been on (anti-)estrogenic and (anti-)androgenic effects, and these effects are thought to be mediated through the estrogen (ER) and androgen (AR) receptors, respectively. The seriousness of the problem has led international bodies such as the Organization for Economic Cooperation and Development (OECD) and the European Union (EU) to initiate large research programs and developments toward new guidelines and regulations. EDCs have both synthetic and natural sources. The mechanisms of action of EDCs can be divided into: (1) agonistic/antagonistic effect ("hormone mimics"), (2) disruption of production, transport, metabolism, or secretion of natural hormones, and (3) disruption of production and/or function of hormone receptors. However, the number of nuclear hormone receptors being potential targets for EDCs has increased dramatically the last decade, opening up new avenues for possible endocrine disruptor effects. In studies with Atlantic salmon, data showed that 4-nonylphenol, a model xenoestrogen previously used in large volumes, for example, in paints and detergents, acts as an estrogen mimic, as a steroid metabolism disruptor, and by modulating estrogen receptor (ER) levels, indicating that one single compound exerts all of these three mechanisms, depending on the dose given to the organism. A hypothesis explaining this observation is that the nature of the effect of an EDC is determined by dose-dependent routing and cross-talk between different classes of nuclear receptors.

Animals↗
PubMed1999

Antiestrogens--tamoxifen, SERMs and beyond.

Estrogens play a central role in reproductive physiology. The cellular effects of estrogens are mediated by binding to nuclear receptors (ER) which activate transcription of genes involved in cellular growth control. At least two such receptors, designated ERalpha and ERbeta, mediate these effects in conjunction with a number of coactivators. These receptors can directly interact with other members of the steroid receptor superfamily. A complex cross-talk exists between the estrogen-signaling pathways and the downstream signaling events initiated by growth factors, such as epidermal growth factor and insulin-like growth factors. Estrogens are also a causative factor in the pathogenesis of a variety of neoplastic and non-neoplastic diseases, including breast cancer, endometrial cancer, endometriosis, and uterine fibroids, among others. Antiestrogens, such as tamoxifen, are widely used for the treatment of breast cancer. Tamoxifen produces objective tumor shrinkage in advanced breast cancer, reduces the risk of relapse in women treated for invasive breast cancer, and prevents breast cancer in high-risk women. Although, initially developed as an antiestrogen, tamoxifen can also prevent postmenopausal osteoporosis as well as reduce cholesterol, due to its estrogen-agonist effects. Its estrogen-agonist activity, however, can lead to significant side-effects such as endometrial cancer and thromboembolic phenomena. This has led to the concept of "ideal" selective estrogen receptor modulators (SERMs), drugs that would have the desired, tissue selective, estrogen-agonist or -antagonist effects. Raloxifene is a SERM which has the desirable mixed agonist/antagonist effects of tamoxifen but does not cause uterine stimulation. "Pure" antiestrogens may provide very potent estrogen-antagonist drugs, but are likely to be devoid of beneficial effects on bone and lipids. Future drug development efforts should focus on developing superior SERMs that have a greater efficacy against ER-positive tumors and do not cause hot flashes or thromboembolism, and explore combination strategies to simultaneously target hormone-dependent as well as hormone-independent breast cancer.

Animals↗
PubMed1998

Modulation of estrogen receptor gene expression in human breast cancer cells: a decoy strategy with specific PCR-generated DNA fragments.

Transcriptional activity of human estrogen receptor (hER) gene was modulated by competition with double-stranded PCR-generated DNA fragments (decoys) that contain 5' upstream sequences of the hER gene. Two DNA fragments belonging to the P1 canonical promoter and the P3 distal promoter, 120 and 102 bp in size respectively, were produced by PCR and directly transfected in MCF7 breast cancer cells. After 24 hours transfection, RT-PCR analysis revealed that the 120 bp decoy significantly reduced the expression of the ER gene and estrogen responsive genes (PR and c-myc), whereas the 102 bp decoy increased the ER mRNA level. An ER unrelated PCR product, used as control, had no activity. The biological activity of these ds DNAs was related to their high stability, binding affinities, and lack of cytotoxicity. These findings suggest that such PCR product decoys may be a non-antisense tool to analyze putative regulatory sequences and to study the function of DNA-binding transcription factors.

Breast Neoplasms↗
PubMedDate not supplied

Inhibition of low-density lipoprotein oxidation by the pure antiestrogens ICI 182780 and EM-652 (SCH 57068).

OBJECTIVE: The use of modulators of estrogen receptors activation is receiving increasing interest in menopausal medicine. Pure antiestrogens define a group of compounds exhibiting universal antagonistic properties. Nevertheless, we cannot disregard the possibility that they may still have some agonistic actions. Because estradiol (E2) has antioxidant properties, we tested the antioxidant capacity of two pure antiestrogens, ICI 182780 and EM-652 (SCH 57068). DESIGN: The ability of both compounds to protect isolated low-density lipoproteins against copper-induced oxidation in vitro was used as an index of their antioxidant properties. RESULTS: When compared with control (vehicle alone), ICI 182780 and EM-652 significantly increased the lag time of low-density lipoprotein oxidation when present at concentrations of 10 and 0.5 microM or greater, respectively. When compared with estrogens, ICI 182780 was as effective as E2 at the lower concentrations tested (0.1 and 1 microM) but less effective at higher concentrations. EM-652 had similar antioxidant potency as E2 but exerted maximal effects at lower concentration. Combined exposure to E2 and each of the antiestrogens resulted in a higher antioxidant effect than that of antiestrogen alone. Another estrogen (estrone), and selective estrogen-receptor modulators, such as tamoxifen and hydroxytamoxifen, displayed an antioxidant potency that was close to ICI 182780 but lower than EM-652. Progestogens, such as progesterone or medroxyprogesterone acetate, had no antioxidant effect. CONCLUSIONS: Both ICI 182780 and EM-652 exhibited potent antioxidant activity, which could have important biological implications.

Antioxidants↗
PubMed2004

Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Delta3 on estrogenic ligands with different intrinsic activity.

The nuclear receptor coactivator amplified in breast cancer 1 (AIB1) and its more active isoform AIB1-Delta3 are overexpressed in breast cancer and preneoplastic breast tissue. However, the impact of these proteins on the transcriptional activity of natural estrogens or selective estrogen receptor modulators (SERMs) has not been determined. Here we show that AIB1-Delta3 causes a significant increase in the efficacy of 17beta-estradiol at both estrogen receptor-alpha (ER-alpha) and ER-beta in ovarian, breast and endometrial cancer cell lines. AIB1-Delta3 also significantly increased the efficacy of the natural estrogen genistein at both ER-alpha and ER-beta, whereas AIB1 had no effect on either the potency or efficacy of genistein at either receptor. The estrogenic efficacy of the partial agonist tamoxifen was significantly increased in all cell lines at ER-alpha by overexpression of AIB1-Delta3 both on transfected and endogenous estrogen responsive genes. In contrast, overexpression of AIB1 or AIB1-Delta3 had no effect on the potency or efficacy of the SERM raloxifene. We conclude that overexpression of the AIB1-Delta3 isoform will increase the estrogenicity of a variety of natural and pharmacologic compounds in tissues that develop hormone-dependent neoplasias and overexpression of these cofactors may be a contributing factor to the hormone-driven development of neoplasia and to antiestrogen resistance of breast cancers.

Breast Neoplasms↗
PubMedDate not supplied

Oestrogenic activity of isobutylparaben in vitro and in vivo.

The alkyl esters of p-hydroxybenzoic acid (parabens) are used widely as preservatives in foods, pharmaceuticals and cosmetics to which the human population is exposed. Recent studies have reported that methylparaben, ethylparaben, n-propylparaben and n-butylparaben all possess oestrogenic activity in several in vitro assays and in animal models in vivo. This study reports on the oestrogenic activity of isobutylparaben in a panel of assays in vitro and in vivo. Isobutylparaben was able to displace [(3)H]oestradiol from cytosolic oestrogen receptor alpha of MCF7 human breast cancer cells by 81% at 100 000-fold molar excess. Using a clonal line of MCF7 cells containing a stably transfected oestrogen-responsive ERE-CAT reporter gene, CAT gene expression could be increased by isobutylparaben such that the magnitude of the response was the same at 10(-5) M isobutylparaben as with 10(-8) M 17beta-oestradiol. Isobutylparaben could also increase expression of the endogenous oestrogen-responsive pS2 gene in MCF7 cells and maximal expression at 10(-5) M isobutylparaben could be inhibited with the anti-oestrogen ICI 182 780. The proliferation of two oestrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1 could be increased with isobutylparaben such that at concentrations of 10(-5) M the proliferation response was of the same magnitude as with 10(-8) M 17beta-oestradiol. Evidence for oestrogen receptor mediation of proliferation effects was provided by the inability of isobutylparaben to influence the growth of oestrogen-unresponsive MDA-MB-231 human breast cancer cells and by the ability of the anti-oestrogen ICI 182 780 to inhibit the isobutylparaben effects on MCF7 cell growth. The proliferation response to 10(-10) M 17beta-oestradiol was not antagonized with isobutylparaben at any concentration from 10(-9) M to 10(-4) M in either MCF7 or ZR-75-1 cells. Finally, subcutaneous administration of isobutylparaben was able to increase the uterine weight in the immature mouse after three daily doses of 1.2 or 12.0 mg per mouse. Previous work using linear-alkyl-chain parabens has shown that oestrogenic activity increases with alkyl chain length from methylparaben to n-butylparaben. The results here show that branching of the alkyl chain to isobutylparaben increases oestrogenic activity beyond that of the equivalent length linear alkyl chain in n-butylparaben.

Animals↗