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PubMed2004

Belamcanda chinensis and the thereof purified tectorigenin have selective estrogen receptor modulator activities.

Belamcanda chinensis (BC) belongs to the family of iridaceae and the isoflavone tectorigenin has been isolated from the rhizome of this plant. Whether this isoflavone has estrogenic, possibly selective estrogen receptor modulator activities and if so, whether they are mediated via the estrogen receptor alpha or beta is unknown at present. Therefore, we performed binding studies with recombinant human ERalpha and ERbeta to show that tectorigenin binds to both receptor subtypes. In ERalpha-expressing MCF7 and ERbeta-expressing MDA-MB231 reporter gene transfected cells tectorigenin causes transactivation. When given intravenously to ovariectomized (ovx) rats, it inhibits pulsatile pituitary LH secretion. In postmenopausal women estrogen-unopposed LH pulses correlate with hot flushes. Therefore, suppression of pulsatile LH secretion may be beneficial in women suffering from hot flushes. Upon chronic application to ovx rats a BC extract containing 5% Belamcanda at a daily dose of 33 mg or 130 mg of the extract had no effect on uterine weight or on estrogen-regulated uterine gene expression while estrogenic effects in the bone, on bone mineral density of the metaphysis of the tibia could be established. Hence, tectorigenin may have antiosteoporotic effects also in postmenopausal women. Immunohistochemical staining of proliferating cell nuclear antigen--a proliferation marker--in the mammary gland did not indicate a mammotrophic effect of the tectorigenin-containing BC extract at both tested doses. In summary, tectorigenin or the B. chinensis extract containing tectorigenin had a strong hypothalamotropic and osteotropic effect but no effect in the uterus or the mammary gland. Therefore, tectorigenin may be in the future a clinically useful selective estrogen receptor modulator.

Animals↗
PubMed1999

Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women.

Raloxifene hydrochloride (HCl) is a selective estrogen receptor modulator with estrogen agonist effects on bone and lipid metabolism and estrogen antagonist effects on reproductive tissues. Animal studies suggest that raloxifene may affect brain function as well, although the effects of raloxifene on the human brain remain to be established. This paper presents an early safety assessment of raloxifene effects on cognition and mood in postmenopausal women participating in a randomized, double-blind osteoporosis treatment trial. Psychometric test batteries were administered to postmenopausal women at baseline and 1, 6, and 12 months after initiating treatment with raloxifene (60 and 120 mg/day). The Memory Assessment Clinics (MAC) battery and Walter Reed Performance Assessment Battery (PAB) were used to assess multiple and independent aspects of cognitive function, while mood was assessed with the Geriatric Depression Scale (GDS). After 12 months of treatment, there were no significant differences between the raloxifene groups and placebo on performance in either the MAC battery or the PAB. The only significant difference observed was a slight increase in performance favoring the raloxifene 120 mg/day group in an assessment of verbal memory on the MAC battery after 1 month of treatment. Scores on the GDS and the self-reported incidence of mood-related events were not different between treatment groups at any of the assessment periods. These data do not suggest that raloxifene impairs cognition or affects mood in postmenopausal women treated for 1 year. Studies to further assess the safety and potential efficacy of raloxifene with respect to cognitive function are ongoing.

Adult↗
PubMed2006

Antioxidant defense system during endometrial receptivity in the guinea pig: effect of ormeloxifene, a selective estrogen receptor modulator.

The role of the antioxidant defense system during endometrial receptivity, a phenomenon crucial for implantation and decidualization, and the effect of ormeloxifene, a selective estrogen receptor modulator, were investigated in the guinea pig, a laboratory mammalian species with interstitial implantation and a long functional luteal phase during each estrous cycle. A sharp rise in the activity of superoxide dismutase (SOD) in both antimesometrial (AM) and mesometrial segments and peroxidase in the AM segment of the uterus was observed on the day of maximal endometrial receptivity. Pretreatment with ormeloxifene resulted in loss of endometrial responsiveness, as evidenced by inhibition of trauma-induced decidualization and the activity of ornithine decarboxylase, a marker of tissue growth and repair. This was associated with a decrease in SOD and estradiol dehydrogenase activities, with corresponding increases in estrone dehydrogenase activity and stimulation of uterine luminal epithelial cell height and a distension of the uterine and glandular lumen. A decrease in peroxidase activity was observed only in the AM segment of the uterus on the imminent day of maximal endometrial receptivity. No effect on peripheral plasma progesterone concentration or surface ultrastructure was evident. These findings demonstrate that SOD plays an important role, with peroxidase having a supplementary role, in the first line of defense against superoxide anion radicals during the period of maximal endometrial receptivity in the guinea pig. Inhibition of endometrial receptivity and decidualization by ormeloxifene administered during the pre-receptive phase appears to be due to a depressed antioxidant defense system via dysregulation of redox-sensitive signaling, resulting in altered cellular toxicity due to increased superoxide radicals, and might contribute to the contraceptive action of ormeloxifene. This might be related to its estrogen antagonistic activity and/or decreased bioavailability of estradiol at a cellular level due to its increased metabolism to biologically less-active estrone via activation of estradiol-17 beta-hydroxysteroid dehydrogenase and suppression of estrone-17 beta-hydroxysteroid dehydrogenase.

Animals↗
PubMed2002

Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor.

Selective Estrogen Receptor Modulators (SERMs) are a new class of drugsthat bind to estrogen receptor (ER) and elicit agonistic or antagonistic responses, depending on the target tissue. We have developed an in vitro system in which some SERMs (4-hydroxytamoxifen and resveratrol) demonstrate estrogenic response through wild-type (wt) ER, whereas others (raloxifene and GW7604) remain antiestrogenic. This system mimics the tamoxifen-resistant phenotype in clinic, when resistant tumors contain wtER. We used Atlas cDNA arrays to study gene expression profiles after ER activation by different SERMs in MDA-MB-231 human breast cancer cells stably transfected with wtER. Cells were treated with estradiol, four different SERMs, and the pure antiestrogen ICI 182,780. The obtained expression data were analyzed using GeneSpring software. Real-time reverse transcription-PCR was used to verify the array data. Our results showed that treatment with various compounds altered the expression of a diverse group of genes, revealing sets of overlapping genes that may represent a complex network of genes of interrelated signal transduction pathways. Sets of "agonistic" and "antagonistic" genes were identified on the basis of the known response to different SERMs. Further analysis of selected sets of genes revealed functionally related group of genes in each set, encoding proteins that were related to cell proliferation, survival, and apoptosis. Flow cytometry data indicated an antiapoptotic activity in cells treated with agonists versus apoptotic activity in cells treated with antagonists. A model for estradiol-like (survival) and antiestrogen-like (apoptosis) activities of SERMs on the basis of their gene expression profiles is suggested.

Breast Neoplasms↗
PubMed2001

Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulation.

Raloxifene possesses a complex pharmacology with tissue-selective estrogen agonist and antagonist effects. At the center of these effects resides the high affinity interaction of raloxifene with the ER. The ability of raloxifene to compete with estrogen for ER binding accounts for the estrogen antagonist effects of raloxifene in uterine and mammary tissue. Since the precise mechanism for the agonist effect of estrogen on the skeleton remains uncertain, it is difficult to unequivocally cite a single estrogen-like mechanism for raloxifene in bone. However, multiple lines of evidence clearly indicate that the estrogen agonist effect of raloxifene on bone is also mediated via an interaction with ER. The data showing non-additivity of raloxifene and estrogen effects in bone, and those showing the requirement for a pituitary hormone in the anti-estrogenic action of raloxifene and estrogen are particularly important. Thus, global evaluation of the similarities and parallel responses of raloxifene and estrogen in bone and the cardiovascular system, as summarized above, strongly support a similar mechanistic basis for the agonist effects of these agents on the skeleton.

Animals↗
PubMed2004

Cardiovascular actions of selective estrogen receptor modulators and phytoestrogens.

Cardiovascular disease is the leading cause of death among men and women in Western societies. Over the past decade, interest in a better understanding of gender differences in cardiovascular disease has heightened. Concomitantly, the use of hormone therapy for cardiovascular risk reduction in postmenopausal women has come into question in light of recent landmark clinical studies casting doubt on the benefits of this therapy. As a consequence, alternatives to conventional hormone replacement, including selective estrogen receptor modulators and phytoestrogens, have attracted considerable attention. The authors provide an up-to-date review of the clinical actions of selective estrogen receptor modulators on cardiovascular disease. The actions of tamoxifen, raloxifene, droloxifene, and soy phytoestrogens are discussed in the context of cardiovascular disease epidemiology, coronary events, clinical markers of cardiovascular risk, and vascular function. In addition, the authors' current understanding of the mechanism of action of these agents is discussed and recommendations for clinical practice are reviewed.

Arteriosclerosis↗
PubMed2001

Sex hormones and the selective estrogen receptor modulator tamoxifen modulate weekly body weights and food intakes in adolescent and adult rats.

This study documented the effect of changes in male and female sex hormones and the selective estrogen receptor modulator (SERM) tamoxifen on weight gain and food consumption of rats from puberty to adulthood, and assessed whether age at onset of treatment affected outcome. In Study 1, male and female WKY rats were either neutered or sham-operated before puberty, and a subgroup of neutered females underwent estrogen replacement (ERT) at the age of puberty. In Study 2, subgroups of neutered females received either ERT or tamoxifen beginning well into the postpuberty period. Weekly body weight and food consumption were assessed, and food consumption was normalized to metabolic weight (body weight(0.67)). Neutering reduced the rate of weight gain in males (P < 0.05), but significantly increased it in females (P < 0.0001). ERT immediately reduced weight gain and prevented any further increase, resulting in weights below that of sham-operated females (P < 0.05). Tamoxifen prevented further weight gain and returned profiles to that of sham-operated females. Food consumption, normalized to metabolic weight, was similar in females and males, and both sexes showed a decrease through maturation to adulthood. Neutering decreased food consumption below that of sham-operated animals in both males and females (P < 0.05), and ERT returned it to sham levels. Despite the fact that tamoxifen had an effect on body weight similar to that of ERT, females receiving tamoxifen treatment consumed less food than both sham-operated and ERT females (P < 0.05). Weight gain is modulated by sex hormones in male and female rats, with both estrogen and tamoxifen exerting immediate effects in females, irrespective of the age at which treatment is initiated. Differences in food consumption do not appear to account for the effects of hormones and tamoxifen on body weight, suggesting that they exert a direct effect on overall body metabolism.

Aging↗
PubMed2000

Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat.

It has been well documented that selective estrogen receptor modulators (SERMs) can prevent bone loss in ovariectomized rats and postmenopausal women. The purposes of this study were to determine the effects of a potent and orally active SERM, lasofoxifene (CP-336,156), on bone mass, bone strength, total serum cholesterol, prostate weight, and histology in adult male orchidectomized (ORX) rats. Sprague Dawley male rats at 10 months of age were divided into 6 groups, with 10 rats/group. The first group was necropsied on day 0 and served as basal controls. The remaining rats were either sham operated (n = 10) and treated orally with vehicle, or ORX (n = 40) and treated with either vehicle or lasofoxifene at 1, 10, or 100 microg/kg x day for 60 days. Total serum cholesterol, prostate weight and histology, distal femoral bone mineral density (DFBMD) by dual energy x-ray absorptiometry, and static and dynamic bone histomorphometry of the third lumbar vertebral body were determined. Maximal load and stiffness of the fifth lumbar vertebral body were also determined by compression tests. Age-related decreases in DFBMD (-9%) and trabecular bone volume (TBV; -13%) of the third lumbar vertebral body were found in sham-operated rats compared with basal controls. ORX induced significant increases in total serum cholesterol (+31%), eroded surface (+48%), activation frequency of bone turnover (+103%) and significant decreases in prostate weight (-89%), DFBMD (-14%), TBV (-23%), and maximal load (-17%) compared with basal controls. Compared with sham controls, ORX induced significant increases in eroded perimeter and activation frequency. Lasofoxifene decreased body weight in all dose groups compared with both sham and ORX control values. Compared with ORX controls, ORX rats treated with lasofoxifene at 10 or 100 microg/kg x day had significantly lower percent eroded perimeter activation frequency and significantly higher DFBMD, TBV, and maximal load. Further, lasofoxifene at 10 and 100 microg/kg x day significantly decreased total serum cholesterol by 46% and 68% in ORX rats, whereas no effect was found in prostate weight and histology parameters compared with ORX control values. These data showed that lasofoxifene prevented bone loss by inhibiting bone turnover associated with aging and orchidectomy in 10-month-old male rats. Further, lasofoxifene decreased total serum cholesterol and did not affect the prostate in these rats. These results suggest that SERMs such as lasofoxifene may be useful therapeutic agents for preventing bone loss in elderly men with some degree of hypogonadism.

Aging↗
PubMed2000

Nitric oxide stimulatory and endothelial protective effects of idoxifene, a selective estrogen receptor modulator, in the splanchnic artery of the ovariectomized rat.

Estrogen is known to stimulate endothelial nitric oxide production and attenuate endothelial dysfunction after ischemia and reperfusion. However, estrogen therapy increases the risk of breast and endometrial cancer. The present study was designed to determine whether idoxifene, a selective estrogen receptor modulator without adverse effects on reproductive organs, may stimulate nitric oxide release and protect endothelial function. In U-46619 precontracted superior mesenteric arterial (SMA) segments isolated from ovariectomized rats, idoxifene and 17 beta-estradiol resulted in a comparable dose-dependent vasorelaxation (maximal relaxation: 75.3 +/- 4.9 and 71 +/- 4.7%, respectively). Treatment of the rings with N(omega)-nitro-L-arginine methyl ester completely blocked idoxifene- and 17 beta-estradiol-induced vasorelaxation. In vitro incubation of SMA rings with TNF alpha significantly reduced vasorelaxation to an endothelium-dependent vasodilator, acetylcholine (maximal relaxation: 73 +/- 3.7 versus 95 +/- 2.9% pre-TNF alpha, P <.01). Idoxifene, but surprisingly not 17 beta-estradiol, prevented TNF alpha-induced endothelial dysfunction (maximal relaxation: 86 +/- 2.6% in idoxifene-treated rings and 77 +/- 5.1% in 17beta-estrogen-treated rings). In vivo ischemia and reperfusion resulted in significant endothelial dysfunction as evidenced by decreased vasorelaxation to acetylcholine (maximal relaxation: 48 +/- 5.5 versus 92 +/- 3.9% in normal SMA rings), but a normal relaxation response to an endothelium-independent vasodilator, acidified NaNO(2) (95 +/- 3.2%). Treatment with idoxifene at either 1 or 2 mg/kg/day, or 17beta-estrogen at 1 mg/kg/day for 4 days significantly preserved endothelial function (P <.01 versus vehicle). Taken together, these results demonstrate that idoxifene is an endothelium-dependent vasodilator and exerts significant endothelial protective effects against TNF alpha- and ischemia-reperfusion-induced endothelial injury. These results suggest that selective estrogen receptor modulators have therapeutic potential in diseases where endothelial dysfunction plays an important role.

Animals↗
PubMed2006

Extracellular matrix integrity: a possible mechanism for differential clinical effects among selective estrogen receptor modulators and estrogens?

Recent gene microarray studies have illustrated heterogeneity in gene expression changes not only between estrogens and selective estrogen receptor modulators (SERMs), but also across different SERM molecules. In ovariectomized rats, this phenomenon was observed with respect to a number of genes involved in collagen turnover and extracellular matrix (ECM) integrity in the uterus and vaginal tissues. Preliminary mechanistic data suggest that these effects on ECM integrity may have relevance in the context of the effect of estrogens and some SERMs to increase the risk of pelvic organ prolapse and the incidence of urinary incontinence in postmenopausal women. Given the pivotal role of ECM integrity and collagen turnover in other tissues and disease states, these processes may provide a fruitful target for future research into the mechanisms for the heterogeneous pharmacology of estrogens and SERMs across different cell types and target tissues.

Animals↗
PubMed2001

Effect of hormone replacement therapies and selective estrogen receptor modulators in postmenopausal women with uterine leiomyomas: a literature review.

This systematic review examines current literature relating to clinical studies of hormone replacement therapy (HRT) and tibolone, including selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene, and their usage in postmenopausal women with fibroids. After a MEDLINE search, 28 relevant articles were found in total, of which five concerned randomized controlled trials. The results from class I studies and class II studies are evaluated in the categories of those that involved tibolone only, those that involved HRT only, and those that involved SERMs such as tamoxifen and raloxifene. In conclusion, tibolone has no significant effect on myoma size in postmenopausal women. There is myoma growth in postmenopausal women taking HRT. However, this does not appear to cause clinical symptoms.

Animals↗
PubMed2002

Tamoxifen but not other selective estrogen receptor modulators antagonizes estrogen actions on luteinizing hormone secretion while inducing gonadotropin-releasing hormone self-priming in the rat.

Selective estrogen receptor modulators (SERMs) are compounds which may function as agonists or antagonists depending upon the target tissue. This study compares the actions of different SERMs on luteinizing hormone (LH) secretion, and on gonadotropin-releasing hormone (GnRH) self-priming in the rat. To do this, 4-day cyclic rats were injected twice, on day 2 (metestrus) and day 3 of the estrous cycle, with one of the following SERMs: 0.25 mg ICI 182,780, 3 mg tamoxifen (TX), LY139481-HCl or LY117018-HCl, or 0.5 mg RU58668. Control rats were given subcutaneous injections of 0.2 ml oil. On the morning of day 4 (proestrus in controls), rats from each group were either injected intraperitoneally with pentobarbital (40 mg/kg) for in vivo study or decapitated and their pituitaries collected for incubation (in vitro study). Additionally, pituitaries taken on each day of the estrous cycle from control rats as well as on day 4 from SERM-treated rats were processed for immunohistochemical determination of the estrogen receptor-alpha (ERalpha) gonadotrope. The plasma concentration or accumulation of LH in the medium was determined after 1 h (basal secretion). Thereafter, an intravenous bolus of GnRH (50 ng/0.5 ml/100 g BW) or 10(-8) M GnRH was injected or added to the medium, respectively. After 1 h of GnRH exposure, blood or medium were taken, and another challenge of GnRH was made. At the end of the 3rd h of the experiment, blood or medium samples were taken again and the LH plasma concentration or accumulation in the medium were determined. All SERM treatments reduced uterus weight and decreased basal and stimulated LH secretion. Also, on day 4, rats treated with any SERM other than TX showed vaginal smears infiltrated by leukocytes and a reduction in GnRH self-priming. TX-treated rats exhibited cornified vaginal smears and an estrogenic effect on GnRH self-priming. Moreover, 15-min exposure to two consecutive GnRH (10(-8) M) challenges 1 h apart in incubated pituitaries with estradiol (E(2), 10(-8) M), TX (10(-7) M), E(2) + TX, or medium alone form ovariectomized rats injected for 3 days with estradiol benzoate (25 microg), TX (3 mg), estradiol benzoate + TX, or 0.2 ml oil, respectively, showed that TX increased GnRH self-priming, as did E(2), whereas it reduced the E(2)-sensitizing effect on GnRH-stimulated LH secretion and cancelled the E(2)-dependent GnRH self-priming. All SERMs prevented the physiological nucleocytoplasmic shuttling of ERalpha exhibited during proestrus in control rats, and TX, in addition, induced a significantly larger number of gonadotropes displaying strong cytosolic immunosignals corresponding to ERalpha than the rest of the experimental groups. Overall, data from this study indicated that, in contrast to the general antagonistic effect of the tested SERMs, TX seemed to display both selective agonist and antagonist activity at the gonadotrope level and on GnRH self-priming of LH secretion respectively.

Animals↗
PubMed2003

Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta.

Estrogens and selective estrogen receptor modulators (SERMs) interact with estrogen receptor (ER) alpha and beta to activate or repress gene transcription. To understand how estrogens and SERMs exert tissue-specific effects, we performed microarray analysis to determine whether ERalpha or ERbeta regulate different target genes in response to estrogens and SERMs. We prepared human U2OS osteosarcoma cells that are stably transfected with a tetracycline-inducible vector to express ERalpha or ERbeta. Western blotting, immunohistochemistry, and immunoprecipitation studies confirmed that U2OS-ERalpha cells synthesized only ERalpha and that U2OS-ERbeta cells expressed exclusively ERbeta. U2OS-ERalpha and U2OS-ERbeta cells were treated either with 17beta-estradiol (E2), raloxifene, and tamoxifen for 18 h. Labeled cRNAs were hybridized with U95Av2 GeneChips (Affymetrix). A total of 228, 190, and 236 genes were significantly activated or repressed at least 1.74-fold in U2OS-ERalpha and U2OS-ERbeta cells by E2, raloxifene, and tamoxifen, respectively. Most genes regulated in ERalpha cells in response to E2, raloxifene, and tamoxifen were distinct from those regulated in ERbeta cells. Only 38 of the 228 (17%) genes were regulated by E2 in both U2OS-ERalpha and U2OS-ERbeta cells. Raloxifene and tamoxifen regulated only 27% of the same genes in both the ERalpha and ERbeta cells. A subset of genes involved in bone-related activities regulated by E2, raloxifene, and tamoxifen were also distinct. Our results demonstrate that most genes regulated by ERalpha are distinct from those regulated by ERbeta in response to E2 and SERMs. These results indicate that estrogens and SERMs exert tissue-specific effects by regulating unique sets of targets genes through ERalpha and ERbeta

Estradiol↗
PubMed2003

Nitrosation, nitration, and autoxidation of the selective estrogen receptor modulator raloxifene by nitric oxide, peroxynitrite, and reactive nitrogen/oxygen species.

The regulation of estrogenic and antiestrogenic effects by selective estrogen receptor modulators (SERMs) provides the basis for use in long-term therapy in cancer chemoprevention and postmenopausal osteoporosis. However, the evidence for carcinogenic properties within this class requires study of potential pathways of toxicity. There is strong evidence for the elevation of cellular levels of NO in tissue treated with SERMs, including the benzothiophene derivative, raloxifene, in part via up-regulation of nitric oxide synthases. Therefore, the reactions of 17beta-estradiol (E(2)), raloxifene, and an isomer with NO, peroxynitrite, and reactive nitrogen/oxygen species (RNOS) generated from NO(2)(-)/H(2)O(2) systems were examined. Peroxynitrite from bolus injection or slow release from higher concentrations of 3-morpholinosydnonimine (SIN-1) reacted with the benzothiophenes and E(2) to give aromatic ring nitration, whereas peroxynitrite, produced from the slow decomposition of lower concentrations of SIN-1, was relatively unreactive toward E(2) and yielded oxidation and nitrosation products with raloxifene and its isomer. The oxidation and nitrosation products formed were characterized as a dimer and quinone oxime derivative. Interestingly, the reaction of the benzothiophenes with NO in aerobic solution efficiently generated the same oxidation products. Stable quinone oximes are not unprecedented but have not been previously reported as products of RNOS-mediated metabolism. The reaction of glutathione (GSH) with the quinone oxime gave both GSH adducts from Michael addition and reduction to the corresponding o-aminophenol. The ready autoxidation of raloxifene, observed in the presence of NO, is the first such observation on the reactivity of SERMs and is potentially a general phenomenon of significance to SERM chemical toxicology.

Chromatography, High Pressure Liquid↗
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↗
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 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↗