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PubMed2005

Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides.

Although approved for the treatment of hormone-dependent breast cancer as well as for the prevention of breast cancer in high-risk women, the selective estrogen receptor modulator (SERM) tamoxifen has been associated with an increased risk of endometrial cancer in women. With an understanding of the potential carcinogenic mechanisms of these compounds, SERMs could in principle be designed or selected for use that avoids these problems. Acolbifene (EM-652) is a fourth-generation SERM and the active form of the ester prodrug EM-800. As a pure antagonist of breast tumor development and growth, acolbifene does not stimulate endometrial tissue. However, acolbifene was found in this investigation to form two kinds of quinone methides, either through chemical or through enzymatic oxidation. One was a classical acolbifene quinone methide, which was formed by oxidation at the C-17 methyl group, and the other was a diquinone methide involving the oxidation of two phenol groups. The half-life of the classical quinone methide was determined to be 32 +/- 0.4 s at physiological pH and temperature. The quinone methides reacted with glutathione (GSH) to form five mono-GSH conjugates and five di-GSH conjugates. The majority of GSH conjugates resulted from reaction of the classical acolbifene quinone methide with GSH. Incubations of acolbifene with GSH and either tyrosinase or human and rat liver microsomes also produced acolbifene quinone methide-GSH conjugates. In addition to reaction with GSH, the classical acolbifene quinone methide was also shown to react with deoxynucleosides. One of the major deoxynucleoside adducts was identified as the deoxyadenosine adduct resulting from reaction of the classical acolbifene quinone methide with the exocyclic amino group of adenine. Acolbifene could also induce DNA damage in the S30 breast cancer cell line. These data imply that the classical electrophilic acolbifene quinone methide might contribute to the potential toxicity of acolbifene.

Animals↗

PubMed2005

In vitro bioactivation of dihydrobenzoxathiin selective estrogen receptor modulators by cytochrome P450 3A4 in human liver microsomes: formation of reactive iminium and quinone type metabolites.

Estrogens and selective estrogen receptor modulators (SERMs) are prescribed widely in the clinic to alleviate symptoms in postmenopausal women, and they are metabolized to reactive intermediates, which may elicit adverse effects. As part of our efforts to develop safer SERMs, in vitro covalent protein binding of (2S,3R)-(+)-3-(4-hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol (I) was evaluated. Radioactivity from [3H]I became covalently bound to proteins in a fashion that was both time- and NADPH-dependent in human liver microsomes and reached a value of 1106 pmol equiv/mg protein following a 45 min incubation. At least three pathways are involved in the bioactivation of I, namely, oxidative cleavage of the dihydrobenzoxathiin moiety to give a hydroquinone/para-benzoquinone redox couple, hydroxylation at position 5 or 7 of the benzoxathiin moiety leading to an o-quinone intermediate, and metabolism of the piperidine ring to give an iminium ion. The latter reactive intermediate was identified as its bis-cyano adduct when human liver microsomal incubations were performed in the presence of sodium cyanide. Structural modification of I, including a replacement of the piperidine with a pyrrolidine group, led to (2S,3R)-(+)-3-(3-hydroxyphenyl)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol (II), which did not form a reactive iminium ion. Following the incubation of II with human liver microsomes, covalent binding to proteins was reduced (461 pmol equiv/mg protein), the residual level of binding apparently due to the formation of a rearranged biphenyl quinone type metabolite. Studies with inhibitory antibodies and chemical inhibitors showed that P450 3A4 was the primary enzyme responsible for oxidative bioactivation of I and II in human liver microsomes. These studies thus demonstrated that gaining an understanding of bioactivation mechanisms may be exploited in terms of guiding structural modifications of drug candidates to minimize covalent protein binding and, hopefully, to lower the potential for drug-mediated adverse effects.

Benzoquinones↗

PubMed1999

Assay for levormeloxifene, a selective estrogen receptor modulator, in human and monkey plasma employing high-performance liquid chromatography and solid-phase extraction.

Assays for levormeloxifene, a new selective estrogen receptor modulator, and its 7-desmethyl metabolite in human and cynomolgus monkey plasma are described. Plasma was extracted on mixed-mode bonded sorbent material (C8/SCX) and the extracts were analysed by high-performance liquid chromatography with fluorescence detection. Recoveries of levormeloxifene and the metabolite exceeded 70%. Within and total assay precision calculated as a coefficient of variation (C.V.) were <8% for both compounds at all concentration levels, except at the limit of quantitation (LOQ) where the C.V. was 15%. Within and total-assay accuracy calculated as a percentage of the nominal value were between 90 and 114% for both analytes. The LOQ was for levormeloxifene and 7-desmethyllevormeloxifene, respectively, 1.5 and 2.5 ng/ml (man) and 5.2 and 6.9 ng/ml (monkey). In the monkey plasma assay, human plasma could substitute monkey plasma as blank plasma.

Animals↗

PubMed2005

A selective estrogen receptor modulator, tamoxifen, and membrane fluidity of erythrocytes in normotensive and hypertensive postmenopausal women: an electron paramagnetic resonance investigation.

BACKGROUND: Recent studies have shown that tamoxifen, which belongs to a group called selective estrogen receptor modulators (SERM), may exert protective effects against cardiovascular diseases and stroke in postmenopausal women. On the other hand, abnormalities in physical properties of the cell membranes may underlie the defects that are strongly linked to hypertension, stroke, and other cardiovascular diseases. The present study was performed to investigate the effects of tamoxifen on cell membrane fluidity (a reciprocal value of membrane microviscosity) in normotensive and hypertensive postmenopausal women. METHODS AND RESULTS: We used an electron paramagnetic resonance (EPR) and spin-labeling method. Tamoxifen significantly decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (h(o)/h(-1)) for 16-NS obtained from EPR spectra of erythrocyte membranes in normotensive postmenopausal women (mean +/- SEM, order parameter value; control 0.719 +/- 0.002, n = 41; tamoxifen 1 x 10(-7) mol/L 0.704 +/- 0.002, n = 41, P < .0001; tamoxifen 1 x 10(-6) mol/L 0.696 +/- 0.002, n = 41, P < .0001; tamoxifen 1 x 10(-5) mol/L 0.692 +/- 0.002, n = 41, P < .0001). The finding indicated that tamoxifen increased the membrane fluidity and improved the membrane microviscosity of erythrocytes. The membrane action of tamoxifen was antagonized by the estrogen receptor antagonist ICI 182,780. The effect of tamoxifen was significantly potentiated by the nitric oxide (NO) donors, l-arginine and S-nitroso-N-acetylpenicillamine, and a cGMP analog 8-bromo-cGMP. In contrast, the change evoked by tamoxifen was counteracted by the NO synthase inhibitors N(G)-nitro-l-arginine-methyl-ester and asymmetric dimethyl-l-arginine. In hypertensive postmenopausal women, the membrane fluidity of erythrocytes was significantly lower than in normotensive postmenopausal women. The effect of tamoxifen on the membrane fluidity was more pronounced in hypertensive postmenopausal women than in normotensive postmenopausal women. CONCLUSIONS: These results showed that tamoxifen increased the membrane fluidity of erythrocytes and improved the rigidity of cell membranes in postmenopausal women, to some extent, through the NO- and cGMP-dependent mechanisms. Furthermore, the greater effect of tamoxifen in hypertensive postmenopausal women suggests that tamoxifen could have a beneficial effect in regulating the blood rheologic behavior and in the improvement of the microcirculation in hypertension.

Aged↗

PubMed2005

Breast cancer chemoprevention: a review of selective estrogen receptor modulators.

Breast cancer is the most common cancer diagnosis among women in the United States. Chemoprevention plays an important role for women at high risk for developing breast cancer. The use of selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene has demonstrated mixed results in breast cancer prevention clinical trials. In the United States, tamoxifen is approved for use for breast cancer prevention in women at high risk. The continued development of SERMs with improved side-effect profiles is needed. Oncology nurses play a pivotal role in helping patients to understand the current status of breast cancer prevention as well as the future direction of research.

Breast Neoplasms↗

PubMedDate not supplied

Expression of steroid receptors in intact rat uterus, mammary gland, and liver treated with selective estrogen receptor modulators and conjugated equine estrogens.

The aim of the present study was to determine the effects of conjugated equine estrogens (CEE) and selective estrogen receptor modulators (SERM) (tamoxifen [TAM] and raloxifene [RAL]) on the expression of steroid receptors-estrogen receptor (ER) and progesterone receptor (PR)-in intact rat uterus, mammary gland, and liver. A total of 24 female rats weighing 250 to 300 g were randomized into 4 groups. Groups 1, 2, 3, and 4 were respectively given conjugated equine estrogen, tamoxifen, raloxifene, and vehicle for a 28-day period. ER and PR expression was detected in tissues of the uterus, mammary gland, and liver. Uterine wet weight and serum estradiol levels were established for all groups. No statistical difference was observed between groups in the ER expression of mammary gland and liver and in the PR expression of uterus, mammary gland, and liver, but differences were noted in serum estradiol levels and uterine ER expression. Serum estradiol levels were lower in the TAM-treated group; differences between the TAM-treated group and the other groups were statistically important (P<.05). Uterine ER expression was greater in the CEE-treated group; differences between the CEE-treated group and the TAM- and RAL-treated groups were statistically important (P<.05). CEE or SERM versus vehicle treatment in controls did not seem to result in statistically important differences in ER and PR expression in intact rat uterus, mammary gland, and liver. Only ER expression in the uterus was found to be greater in the CEE-treated group than in SERM-treated groups.

Animals↗

PubMed2002

Selective estrogen receptor modulators as a new therapeutic drug group: concept to reality in a decade.

This article provides an overview of the historical development, current research, clinical benefits, and potential future applications of the selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene. The understanding of the mechanism of action of SERMs led not only to the development of tamoxifen, the first widely used antiestrogen for breast cancer treatment, but also to its application as a chemopreventive agent. The SERM principle of antiestrogenic actions in the breast but estrogenlike actions in bone is reviewed in clinical practice through analysis of the current applications and the potential for expanding the role of SERMs. The current view of the molecular mechanism of SERM action is summarized to identify potential target sites for future research. The clinical success of tamoxifen and raloxifene for the prevention and treatment of breast cancer and osteoporosis, respectively, has encouraged the development of a range of new agents that target breast cancer, osteoporosis, coronary heart disease, and endometrial safety.

Anticarcinogenic Agents↗

PubMedDate not supplied

Effects on asymmetric dimethylarginine of HMR 3339, a novel selective estrogen receptor modulator: a 12-week, randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women.

OBJECTIVE: To investigate the short-term effects of three different doses of the selective estrogen receptor modulator HMR 3339 in comparison with placebo and raloxifene on asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor. DESIGN: This study was a multicenter, randomized, placebo-controlled, double-blind, dose-ranging study. Ninety-four healthy postmenopausal women received daily doses of either placebo (n=16), HMR 3339 2.5 mg (n=20), HMR 3339 10 mg (n=19), HMR 3339 50 mg (n=20), or raloxifene 60 mg (n=19) for 12 weeks. Fasting plasma concentrations of ADMA, arginine, and symmetric dimethylarginine (SDMA) were measured at baseline and after 4 and 12 weeks by high-performance liquid chromatography. RESULTS: HMR 3339 induced a dose-dependent reduction of ADMA and SDMA concentrations, with the largest effects (P<0.01 for both) in the HMR 3339 50 mg group compared with baseline and placebo (at 12 weeks: -7.0% [95% CI, -14.2% to 0.2%] for ADMA and -16.2% [95% CI, -22.4% to -10.0%] for SDMA). Twelve weeks of raloxifene 60 mg significantly reduced SDMA (P=0.03) but not ADMA concentrations. Arginine concentrations were not altered by any treatment. CONCLUSIONS: The reduction of the nitric oxide synthase inhibitor ADMA by HMR 3339 may potentially have a beneficial effect on the cardiovascular system in postmenopausal women.

Administration, Oral↗

PubMed2002

Selective estrogen receptor modulators inhibit the effects of insulin-like growth factors in hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (HPT) predominantly affects perimenopausal women, leading to speculations that an estrogen imbalance may be liable. We have previously demonstrated the importance of the insulin-like growth factor (IGF) axis in HPT. Because the antiestrogen tamoxifen has been shown to modulate the IGF axis, we examined the interactions of selective estrogen receptor modulators (SERMs) and IGF in HPT. METHODS; Estrogen receptors were evaluated by Western immunoligand blotting. Sixteen parathyroid glands from 19 patients were included. After adhesion, the cells were treated with IGF (I or II) +/- estrogen +/- SERMs (tamoxifen, ICI 182,780) for 96 hours in serum-free media. Proliferation was assessed by measuring tritiated thymidine incorporation. RESULTS: Both primary and secondary HPT express estrogen receptors alpha and beta. Primary and secondary HPT had comparable responses to SERMs, they were analyzed together. Compared with control (100%), IGFs (I and II) induced a significant increase in DNA synthesis. Estradiol at 10(-8) and 10(-7) mol/L (physiologic range) had no significant effects on IGF (I and II, P >.05). Both tamoxifen and ICI 182,780 inhibited basal DNA synthesis (P <.05) and abolished the effects of both IGF I and II (P <.05). CONCLUSIONS: SERMs are capable of reducing basal and IGF-stimulated DNA synthesis. This reduction in proliferation has implications for cancer biology and therapeutic potential for SERMs in HPT.

Adenoma↗

PubMed2003

The role of selective estrogen receptor modulators (SERMs) in postmenopausal health.

Concerns about long-term therapy with HRT have recently highlighted interest in a class of compounds active in the estrogen receptor, but with selectivity in their actions, known as the selective estrogen receptor modulators (SERMs). Tamoxifen is recognized as the first widely marketed SERM, but its selectivity focuses interest on its approved indications: the treatment and prevention of breast cancer. Raloxifene has been approved in most countries of the world for the treatment and prevention of osteoporosis, and it displays a pattern of actions highly matched to the needs and concerns of many postmenopausal women. Further study of current and future SERMs promises to open new vistas in patient-specific management of the field of postmenopausal health.

Aged↗

PubMed2002

Characterization of selective estrogen receptor modulator (SERM) activity in two triarylethylene oxybutyric acids.

Previously we identified 4-[1-(4-hydroxyphenyl)-2-phenylbuten-1-yl]phenoxy-n-butyric acid (4HBA) and its des-hydroxy analog (BA) as potential selective estrogen receptor modulators (SERMs) in the ovariectomized (OVX) rat. The aim of the present study was to characterize comprehensively the effects of 4HBA and BA in both the OVX rat and in estrogen-responsive cells. Thus, 4HBA was found to be an estrogen antagonist with partial agonist efficacy in estrogen-responsive reporter gene and estrogen-dependent proliferation assays (MVLN cells and MCF-7 human breast cancer cells, respectively). In the OVX rat, 4HBA and BA were equally effective and comparable to other known SERMs regarding (a) serum cholesterol reduction and suppression of serum markers of excessive bone metabolism, and (b) partial agonist efficacy in reproductive tissue relative to steroidal estrogens. Like steroidal estrogens, both compounds increased serum triglyceride levels, with BA being more effective in this regard. The maximal effects of 4HBA on all of these parameters except cholesterol lowering were seen at oral doses of 0.4 micromol/kg/day; maximal cholesterol lowering required doses of 10 micromol/kg/day. In OVX rat liver 9S fraction, BA was found to be efficiently converted to a single hydroxylated metabolite, 4HBA. These results suggest that the effects of BA in the OVX rat might, in part, be a consequence of biotransformation to 4HBA, and that those of 4HBA and BA in the OVX rat and in estrogen-responsive cells are qualitatively similar to those of SERMs such as tamoxifen and raloxifene.

Animals↗

PubMed2003

Associated response in bone mineral density and atherogenic lipid profile during treatment with two different selective estrogen receptor modulators: levormeloxifene and raloxifene.

OBJECTIVE: We recently demonstrated a correlation between the responses in two target areas, bone and lipids, during treatment with hormone replacement therapy. Whether the same association exists during treatment with selective estrogen receptor modulators (SERMs) has not been examined before. STUDY DESIGN: This was an exploratory, post hoc analysis of data from two randomized, double-blind, placebo-controlled trials. STUDY POPULATION: From both studies we examined only the Danish subpopulation. Study 1 included 133 women treated with placebo or levormeloxifene in four different doses for 12 months, and study 2 included 248 women treated with raloxifene in three different doses or placebo for 24 months. MEASUREMENTS: Bone mineral density (BMD) of the spine and hip was measured semiannually. Serum lipids and biochemical bone markers were determined at each visit. To eliminate interindividual differences, all values were calculated as individual percentage change from baseline. RESULTS: We found a significant correlation between the increase in BMD of the spine and hip and the decrease in total cholesterol and low-density lipoprotein. CONCLUSION: Our study showed that, in healthy postmenopausal women, the women with the greatest response in BMD were also those with the most favorable response in lipid profile during treatment with SERMs.

Aged↗

PubMed2002

[Amelioration of ischemia- and reperfusion-induced myocardial injury by the selective estrogen receptor modulator, raloxifene, in the canine heart].

BACKGROUND: 17 beta-estradiol reduces myocardial infarct size which is mediated by nitric oxide (NO) and the opening of Ca (2+)-activated K+ (KCa) channels. Raloxifene, a selective estrogen receptor modulator, demonstrates acute coronary artery vasorelaxing effects. Whether raloxifene reduces ischemia/reperfusion injury and what mechanisms are involved in the cardioprotective effects were investigated. METHODS: Infarct size was measured in open-chest dogs following occlusion of the left anterior descending coronary artery for 90 min and subsequent reperfusion for 6 hr. The incidence of ventricular fibrillations during reperfusion period was also observed. Infusion of raloxifene and/or other drugs into the left anterior descending coronary artery was initiated 10 min before coronary occlusion and continued until 1 hr after reperfusion started without an occlusion period. RESULTS: Infarct size was reduced in the raloxifene (5 micrograms/kg/min) group compared with the control group (6.8 +/- 4.2% vs 40.9 +/- 3.9% of the area at risk, p < 0.01). Either NG-nitro-L-arginine methyl ester, the inhibitor of NO synthase (infarct size: 22.8 +/- 5.4%, p < 0.05 vs raloxifene or the control) or charbdotoxin, the blocker of KCa channels (infarct size: 23.5 +/- 5.1%, p < 0.05 vs raloxifene or the control), partially attenuated the infarct size-limiting effect, and combination of both agents completely abolished the effect (infarct size: 37.7 +/- 5.8%). The incidence of ventricular fibrillations was also less in the raloxifene group than in the control group(11% vs 44%, p < 0.05). CONCLUSIONS: Raloxifene reduces myocardial infarct size and the incidence of ventricular fibrillations by NO- and the opening of KCa channels-dependent mechanisms in canine hearts.

Animals↗

PubMed2006

Effects of selective estrogen receptor modulator raloxifene plus 17-beta estradiol in aorta and mammary gland of female experimental atherosclerosis rabbits and possible involvement of ERK signal transduction pathway.

The present study investigated the effects of raloxifene, a second generation selective estrogen receptor modulator (SERM), plus 17-betaE2 on aortic atherosclerosis and mammary gland hyperplasia in ovariectomized, cholesterol-fed rabbits. Following 10 weeks of raloxifene, 17-betaE2, or raloxifene plus 17-betaE2 administration, serum total cholesterol, triglyceride, low density lipoprotein were significantly decreased in the drug groups compared to the placebo group. Consistent with serum lipid results, the total lesion area for each aorta of the drug groups decreased significantly as compared to the placebo group. HE staining of aorta paraffin section showed that in the drug groups the endothelial monolayer was almost continuous. While in mammary gland, HE staining of paraffin sections indicated the hyperplasia of epithelial cells (in 17-betaE2 group) was obviously inhibited in raloxifene plus 17-betaE2 group. In cultured vascular smooth muscle cell (VSMC), the results of MTT and [3H]TdR incorporation showed that the drug groups could inhibit AngII-induced proliferation of VSMC. Western blotting proved that raloxifene plus 17-betaE2 inhibited the expression of phosphorylated ERK protein, similar to 17-betaE2 but different from raloxifene. This effect was inhibited by PD98059 (inhibitor of MAPK) or ICI182780 (ER antagonist). In conclusion, this study suggests that SERM raloxifene plus 17-betaE2 improves the lipid metabolism and relieves the aorta changes of female experimental atherosclerosis rabbits, which are partly implemented by the inhibition of VSMC growth through ERK cascade. The hyperplasia of mammary gland epithelial cells could be significantly inhibited by raloxifene plus 17-betaE2.

Animals↗

PubMed2005

Effect of the selective estrogen receptor modulator arzoxifene on repopulation of hormone-responsive breast cancer xenografts between courses of chemotherapy.

Selective inhibition of repopulation of clonogenic tumor cells between courses of chemotherapy has potential to improve the effectiveness of treatment. Here we study arzoxifene, a short-acting selective estrogen receptor modulator, for its potential to inhibit repopulation in estrogen-dependent human breast cancer MCF-7 xenografts between courses of chemotherapy. Proliferation of tumor cells was evaluated by cyclin D1 expression and uptake of 5-bromo-2'-deoxyuridine. Arzoxifene decreased cell proliferation in xenografts. To model adjuvant treatment of human breast cancer, MCF-7 cells were injected s.c. into nude mice and four groups of mice received the following treatments beginning after implantation: (a) control (vehicle solution); (b) arzoxifene alone, 5 days per week by oral gavage for 3 weeks; (c) 5-fluorouracil (5-FU) or paclitaxel i.p. weekly, for 3 doses; and (d) arzoxifene following each cycle of chemotherapy. The incidence of tumors with volume > or =50 mm(3) was determined as a function of time. MCF-7 xenografts developed in 100% of control mice by 4 weeks after implantation. Paclitaxel or 5-FU alone had minor effects to delay the appearance of xenografts whereas arzoxifene alone caused longer delay. Combined treatment with arzoxifene given between cycles of 5-FU or paclitaxel had substantial effects, with approximately 50% tumor incidence by 5 weeks. Our results indicate that arzoxifene can inhibit repopulation of hormone-responsive MCF-7 breast cancer xenografts when given between courses of chemotherapy. The scheduling of short-acting hormonal agents between courses of adjuvant chemotherapy for human breast cancer has potential to improve the outcome of treatment.

Animals↗

PubMed2004

Impact of the selective estrogen receptor modulator, tamoxifen, on neuronal outgrowth and survival following toxic insults associated with aging and Alzheimer's disease.

We investigated the estrogen agonist/antagonist properties of the selective estrogen receptor modulators (SERMs), tamoxifen (TMX) and 4-hydroxy-tamoxifen (OHT), using an in vitro neuron model system to determine the impact of the neuroprotective and neurotrophic properties of these SERMs. Low concentrations of TMX or OHT were without effect on a marker of neuronal viability, basal release of lactate dehydrogenase (LDH), whereas high concentrations of both SERMs (2500 ng/ml) induced a significant increase in LDH, indicating the potential toxicity of both SERMs at high concentrations. Subsequent experiments revealed that subtoxic concentrations of both TMX and OHT induced significant neuroprotection against beta-amyloid(25-35)-induced toxicity; 15-20% and 10-15% (P < 0.05), respectively and also against glutamate-induced toxicity; 25-30% and 20-40% (P < 0.05 and P < 0.01), respectively. Additional in vitro experiments included analysis of neuron survival to determine whether the SERM, OHT, acted competitively or synergistically with the endogenous estrogen, 17 beta-estradiol (E2). These revealed that neuron survival following exposure to the neurotoxins beta-amyloid and excitotoxic glutamate was significantly increased in cultures treated with OHT (50 ng/ml) (10%, P < 0.01) and that the magnitude of survival was equivalent to E2 (10 ng/ml). The combined presence of OHT and E2 significantly protected against both beta-amyloid(25-35) and excitotoxic glutamate-induced neuron death (10%, P < 0.01) but was not significantly different from either OHT or E2 alone. To assess neurotrophic effects of these same SERMs, cultured neurons from brain regions involved in memory function and Alzheimer's disease were evaluated by morphological analysis of individual neurons. Results of these analyses demonstrated that TMX treatment did not significantly increase the process outgrowth or morphological complexity of cortical, hippocampal, or basal forebrain neurons. Similar analyses showed that OHT also failed to significantly increase the neuronal outgrowth of either cortical or hippocampal neurons. Results of these studies predict that TMX and OHT could exert a neuroprotective function but would not promote estrogen-dependent memory function.

Aging↗

PubMed2001

The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators.

The human estrogen receptor alpha-isoform (ERalpha) is a nuclear transcription factor that displays a complex pharmacology. In addition to classical agonists and antagonists, the transcriptional activity of ERalpha can be regulated by selective estrogen receptor modulators, a new class of drugs whose relative agonist/antagonist activity is determined by cell context. It has been demonstrated that the binding of different ligands to ERalpha results in the formation of unique ERalpha-ligand conformations. These conformations have been shown to influence ERalpha-cofactor binding and, therefore, have a profound impact on ERalpha pharmacology. In this study, we demonstrate that the nature of the bound ligand also influences the stability of ERalpha, revealing an additional mechanism by which the pharmacological activity of a compound is determined. Of note we found that although all ERalpha-ligand complexes can be ubiquitinated and degraded by the 26 S proteasome in vivo, the mechanisms by which they are targeted for proteolysis appear to be different. Specifically, for agonist-activated ERalpha, an inverse relationship between transcriptional activity and receptor stability was observed. This relationship does not extend to selective estrogen receptor modulators and pure antagonists. Instead, it appears that with these compounds, the determinant of receptor stability is the ligand-induced conformation of ERalpha. We conclude that the different conformational states adopted by ERalpha in the presence of different ligands influence transcriptional activity directly by regulating cofactor binding and indirectly by modulating receptor stability.

Estrogen Antagonists↗

PubMed2006

On-line formation, separation, and estrogen receptor affinity screening of cytochrome P450-derived metabolites of selective estrogen receptor modulators.

We have developed a fully automated bioreactor coupled to an on-line receptor affinity detection system. This analytical system provides detailed information on pharmacologically active metabolites of selective estrogen receptor modulators (SERMs) generated by cytochromes P450 (P450s). We demonstrated this novel concept by investigating the metabolic activation of tamoxifen and raloxifene by P450-containing pig and rat liver microsomes. The high resolution screening (HRS) system is based on the coupling of a P450-bioreactor to an HPLC-based estrogen receptor alpha (ERalpha) affinity assay. P450-derived metabolites of the SERMs were generated in the bioreactor, subsequently trapped on-line with solid phase extraction, and finally separated with gradient HPLC. Upon elution, the metabolites were screened on affinity for ERalpha with an on-line HRS assay. With this HRS system, we were able to follow, in a time-dependent manner, the formation of ERalpha-binding metabolites of tamoxifen and raloxifene. By analyzing the bioaffinity chromatograms with liquid chromatography-tandem mass spectrometry, structural information of the pharmacologically active metabolites was obtained as well. For tamoxifen, 15 active and 6 nonactive metabolites were observed, of which 5 were of primary, 10 of secondary, and 6 of an as yet unknown order of metabolism. Raloxifene was biotransformed in three primary and three secondary metabolites. MS/MS analysis revealed that three of the observed active metabolites of raloxifene were not described before. The present automated on-line HRS system coupled to a P450-containing bioreactor and an ERalpha-affinity detector proved very efficient, sensitive, and selective in metabolic profiling of SERMs.

Animals↗