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Results for “Selective Estrogen Receptor Modulators”

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PubMed2001

Estrogen augments glucose transporter and IGF1 expression in primate cerebral cortex.

Estrogen has many positive effects on neural tissue in experimental model systems, including stimulation of neurite growth and neurotransmitter synthesis and protection against diverse types of neural injury. In humans, estrogen treatment is reputed to protect against Alzheimer's disease. To investigate potential mediators of estrogen's action and determine whether selective estrogen receptor modulators (SERMs) such as tamoxifen have estrogen-like effects in the primate brain, we evaluated the expression of glucose transporters and insulin-like growth factor 1 (IGF1) and its receptor in the frontal cortex of ovariectomized rhesus monkeys. We treated one group for 3 days with vehicle, another with 17 beta estradiol (E2), and a third with tamoxifen. The expression of facilitative glucose transporters (Gluts) 1, 3, and 4 was investigated using in situ hybridization, immunohistochemistry, and immunoblot analysis. Gluts 3 and 4 were concentrated in cortical neurons and Glut1 in capillaries and glial cells. E2 treatment induced two- to fourfold increases in Glut3 and Glut4 mRNA levels and lesser but significant increases in Glut3 and 4 protein levels. E2 treatment induced an approximately 70% increase in parenchymal Glut1 mRNA levels, but did not appreciably affect vascular Glut1 gene expression. IGF1 and IGF1 receptor mRNAs were concentrated in cortical neurons in a distribution similar to Gluts 3 and 4. IGF1 mRNA levels were significantly increased in E2-treated animals but IGF1 receptor mRNA levels were not altered by hormone treatment. Tamoxifen increased cerebral cortical Glut3 and 4 mRNA levels, but did not affect Glut1, IGF1, or IGF1 receptor expression. This study provides novel data showing that Gluts 3 and 4 and IGF1 are coexpressed by primate cerebral cortical neurons, where their expression is enhanced by estrogen. These findings suggest that up-regulation of glucose transporter and IGF1 expression may contribute to estrogen's salutary effects on neural tissue. Tamoxifen, an antiestrogen at the breast, is shown to have estrogen-like effects on higher brain centers in the monkey, suggesting that some SERMs may share estrogen's neuroprotective potential for menopausal women.

Animals↗

PubMed2003

Applicability of the intratumor aromatase preclinical model to predict clinical trial results with endocrine therapy.

Preclinical models and clinical studies have shown that aromatase inhibitors (AIs) are powerful inhibitors of estrogen synthesis and significantly suppress estrogen in vivo. For more than 20 years, standard first-line treatment for postmenopausal women with metastatic breast cancer has been the antiestrogen tamoxifen, a selective estrogen receptor modulator (SERM) with differential effects on breast, endometrial, bone, and vascular tissues. The estrogenic activity of tamoxifen is associated with deleterious clinical side effects, including vaginal bleeding, endometrial cancer, and thromboembolism. AIs are established second-line treatments in patients who progress with tamoxifen. Compared with progestins, such as megestrol acetate, or the earlier AIs aminoglutethimide and fadrozole, the new AIs, including exemestane, anastrozole, and letrozole, have increased efficacy and clinical benefit and cause fewer side effects in patients with metastatic breast cancer. Letrozole and anastrozole are approved first-line therapy for patients with metastatic breast cancer and as second-line treatment after tamoxifen failure. Studies in the intratumoral aromatase xenograft preclinical model have shown better responses with AIs than with antiestrogens in first-line therapy, and these data are consistent with the results from clinical trials. This model is now being used to assess whether combined or sequential administration of AIs with other agents may provide additional benefit.

Anastrozole↗

PubMed2004

Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies.

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 +/- 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n=17), 60 mg raloxifene (n=23), 150 mg raloxifene (n=20) or placebo (n=23) for 24 months. At baseline and after 6, 12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 +/- 2.4 years) randomly received 120 mg raloxifene (n=15) or placebo (n=15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 +/- 0.82 to 2.87 +/- 0.86 at 24 months (P <0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance.

Activated Protein C Resistance↗

PubMed2000

Osteoporosis.

Osteoporosis is a disorder of decreased bone mass, microarchitectural deterioration, and fragility fractures. Osteoporosis is widespread and can affect people of all ethnic backgrounds and many older women and men. An essential element in preventing osteoporosis is the achievement of normal peak bone mass. Adequate nutrition, appropriate calcium and vitamin D intake, regular menstrual cycles and a well balanced exercise program of exercise are essential elements in achieving peak bone mass. At menopause women undergo accelerated bone loss. Thereafter, women and men gradually lose bone mass. A loss of one standard deviation give rise to an enhanced twofold risk of spine fractures or a 2.5 risk of hip fracture. Bone mass is determined by dual energy x-ray absorptiometry, quantitative computed tomography scan, and a peripheral ultrasound. Dual energy x-ray absorptiometry has outstanding precision (within 1% to 2%), and has the ability to show the efficacy of drug intervention. Peripheral measurements may identify osteoporosis but only have a 70% correlation with hip and spine bone mass. Dual energy x-ray absorptiometry determines bone mass in a patient but the bone collagen breakdown products (N-telopeptide crosslinks) establish the current rate of bone loss. Major risk factors leading to fragility fracture include low body weight, history of fracture, family history of osteoporosis, and smoking. All individuals should ingest adequate calcium and vitamin D, exercise, and prevent falls. Women with low bone mass, high urinary bone collagen breakdown products, and/or major risk factors should consider hormone replacement therapy or a selective estrogen receptor modulator (Evista), calcitonin and bisphosphonates (alendronate). These agents successfully increase bone mass and limit fracture risk. Men at risk for fragility fractures respond similarly as women to alendronate and calcitonin. Although vertebral compression fractures can occur spontaneously, hip fractures are attributable to low bone mass coupled with a fall. Hence, fall prevention programs in addition to medical treatment are critical in the prevention of fragility fractures.

Female↗

PubMed2002

Mechanism of raloxifene-induced relaxation in femoral veins depends on ovarian hormonal status.

Experiments were designed to study effects of raloxifene, a selective estrogen receptor modulator, on venous endothelium and smooth muscle. Rings of femoral veins with and without endothelium from adult gonadally intact, and ovariectomized female pigs were suspended for measurement of isometric force in organ chambers. Concentration-response curves to raloxifene (10-9-10-5 M) were obtained in rings at baseline tension or following contraction with prostaglandin (2 x 10-6 M) in the absence or presence of NG-monomethyl-l-arginine (l-NMMA) (nitric oxide synthase inhibitor), 1H-(1.2.4) oxadiazolo (4,3-A) quinoxalin-1-one (ODQ, soluble guanylate cyclase inhibitor), tetraethylammonium acetate (TEA; potassium channel blocker), or indomethacin (cyclooxygenase inhibitor). Raloxifene caused acute, concentration-dependent relaxations that were greater in rings with than in rings without endothelium from both groups. The l-NMMA significantly inhibited relaxations to raloxifene in rings with endothelium from ovariectomized females whereas TEA only inhibited relaxations in rings with endothelium from intact female pigs. ODQ and indomethacin significantly inhibited relaxations in rings with endothelium from both groups. These results suggest that raloxifene acutely relaxes femoral veins through release of endothelium-derived factors and by direct stimulation of vascular smooth muscle cells. Whether nitric oxide or potassium channel activation contributes to relaxations by raloxifene may depend on ovarian hormonal status of the animal.

Animals↗

PubMed2004

Raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart: role of phosphatidylinositol 3-kinase/Akt pathway.

The purpose of this study is to examine whether raloxifene, one of the selective estrogen receptor modulators, could improve myocardial ischemia and to assess the mechanisms involved. In open-chest beagle dogs anesthetized by intravenous infusion of sodium pentobarbital, the left anterior descending coronary artery (LAD) was perfused from the left carotid artery through an extracorporeal bypass tube. Raloxifene was infused into the LAD through the bypass tube under either ischemic or non-ischemic conditions. In the non-ischemic heart, raloxifene had no effect on coronary blood flow, fractional shortening, and myocardial metabolism. However, raloxifene caused an acute increase in both coronary blood flow and fractional shortening, and also improved myocardial anaerobic metabolism in the ischemic heart. These effects were partially attenuated by pretreatment with either L-NAME or wortmannin and were completely abolished by ICI182780 (an estrogen receptor antagonist) or L-NAME plus charybdotoxin (a blocker of Ca-activated K channels). Raloxifene also increased both Akt activity and the NO level, with these changes being completely abrogated by pretreatment with wortmannin. These results demonstrated that raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism by release of NO and opening of Ca-activated K channels in the ischemic heart, and that NO production is mediated by the phosphatidylinositol 3-kinase/Akt pathway.

Animals↗

PubMed1999

Hormone replacement therapy and cardiovascular disease.

A large amount of research continues to be conducted on the mechanisms of hormone replacement therapy (HRT) effects, and the first of the large clinical trials published its results during the past year. In addition to the well known effects on LDL-cholesterol, HDL-cholesterol, and triglycerides, recent studies confirmed that estrogen with or without a progestin lowers lipoprotein (a) concentrations in women (but not in men). In men, estrogen appears to have a similar effect on other lipids and lipoproteins and on plasminogen activator inhibitor-1 as in women. A comparison of estrogen with simvastatin indicated that simvastatin is better at lowering LDL-cholesterol while estrogen is better at raising HDL-cholesterol; when given in combination the additional effects were modest. Estrogen and simvastatin had similar beneficial effects on endothelial function. The estrogen effect on endothelial function may be blocked by medroxyprogesterone, but the data are inconsistent. These studies of intermediate outcomes were put in perspective by the results of a landmark secondary prevention trial of coronary heart disease (CHD). This randomized placebo-controlled trial (Heart and Estrogen/Progestin Replacement Study) of conjugated equine estrogens plus medroxyprogesterone failed to show the anticipated reduction in CHD, and at the same time the threefold increase in venous thromboembolism confirmed that HRT is procoagulant. Therefore, it is still not known whether HRT is a viable option for the prevention of CHD. The preliminary data on selective estrogen receptor modulators are not overly promising, but a definitive trial to test whether raloxifene will reduce CHD is ongoing.

Cardiovascular Diseases↗

PubMed2004

Estrogen in cardiovascular disease.

PURPOSE OF REVIEW: The controversy surrounding hormone replacement therapy has induced fear in patients and left many researchers with the impression that estrogen produces negative effects on cardiovascular function. The aim of this review is to summarize recent findings illustrating that estrogen also has positive effects even if estrogen replacement therapy is not a cure-all. RECENT FINDINGS: Studies have unveiled new aspects of estrogen action in the cardiovascular system; however, clinical trials have not demonstrated a protective effect of the most widely used modalities of hormone replacement therapy against cardiovascular disease. New information has emerged showing that estrogen has both beneficial and detrimental effects. Further mechanistic studies and use of well defined forms of estrogens and selective estrogen receptor modulators will continue to provide novel mechanistic information that will likely lead to the development of new avenues for therapeutic interventions. SUMMARY: Estrogens, like other steroid hormones, are potent actors in the cardiovascular system. Since half the population have high levels of estrogen most of their lives it is plain that estrogen has a variety of beneficial physiologic functions. Clinical studies, however, have demonstrated that a specific formulation of a combination of potent estrogens and metabolites is not a magic bullet, but induces both positive and negative impacts on different organ systems. More research into the mechanistic actions of estrogens in specific pathways in individual cell types is necessary to determine appropriate therapeutic interventions to replace the loss of positive effects of estrogens while minimizing the negative effects in postmenopausal women.

Animals↗

PubMedDate not supplied

Does postmenopausal hormone replacement therapy affect cardiac autonomic regulation in osteoporotic women?

OBJECTIVE: Postmenopausal hormone replacement therapy (HRT) has been associated with reduced risk of cardiovascular disease; however, the mechanisms remain obscure, and it is not known whether this applies to regimens containing both estrogen and progestin. One possibility is that estrogen would act via enhancement of cardiac autonomic regulation. DESIGN: In this prospective, controlled study of 6-months duration, 22 osteoporotic, postmenopausal women in the intervention group were treated with combined estradiol hemihydrate corresponding to estradiol 2 mg and norethisterone acetate 1 mg with or without clodronate (HRT group). Nine women in the control group received clodronate only. Indices of heart rate variability (HRV) by power spectral analyses and baroreceptor sensitivity (BRS) by phenylephrine test were measured before and after 3 and 6 months of treatment. RESULTS: The total power of HRV remained identical within the groups, although it was higher at 3 and 6-month measurements in the control group than the HRT group. This was mainly due to lower very low frequency and high frequency power in the HRT group. However, no changes in the low frequency/high frequency-ratio of HRV, an index of sympathovagal balance, were observed between and within the groups. Further, during the intervention, no significant changes in BRS (baseline and 6 months: 5.0 +/- 2.1 and 5.1 +/- 2.5 ms/mmHg) within the HRT group was observed. CONCLUSIONS: The impact of estrogen and progesterone on cardiac autonomic regulation seems to be quite modest. Therefore, cardiac morbidity and mortality are probably not mediated by their effects on cardiac autonomic regulation. However, the effects of estrogen alone or more selective estrogen receptor modulators need yet to be clarified in future studies.

Anthropometry↗

PubMedDate not supplied

Mammographic changes associated with raloxifene and tibolone therapy in postmenopausal women: a prospective study.

OBJECTIVE: The prolonged use of estrogen therapy is associated with a slightly increased risk of breast cancer. Alternative therapies that are effective in the prevention of menopause, having associated morbidities but no unwanted effects, are of primary interest in the pharmacologic research. The aim of this study was to evaluate the effect of two alternative to estrogens drugs, the selective estrogen receptor modulator raloxifene and the tissue-specific tibolone, on the mammographic appearance of the breast. DESIGN: The study group comprised 131 postmenopausal women aged 41 to 67 years. The women were at least 2 years postmenopausal, free of climacteric symptoms, and at the time of entry to the study had not had therapy for at least 9 months. Women with risk factors for osteoporosis or cardiovascular disease were allocated either to tibolone (n = 56) or raloxifene (n = 48) therapy. Women with no risk factors and women who either did not qualify for or denied treatment (n = 27) served as controls. The study duration was 12 months. Women received a baseline mammogram before commencing therapy and a repeat mammogram at the end of the study period. Mammogram findings were classified according to the modified Wolfe criteria by two expert radiologists. RESULTS: No difference was identified between groups with respect to baseline characteristics associated with breast cancer risk. Similarly, no difference was detected between groups concerning the modified Wolfe classification of baseline mammographic findings. In the tibolone group, 10.7% of the women showed an increase in breast density in the 12-month reevaluation. The respective figure in the raloxifene group was 6.3%, whereas no woman in the control group showed an increase in breast density. Differences in the increase in breast density between groups did not, however, reach statistical significance. Accordingly, 10.7% of women in the tibolone group and 18.8% of women in the raloxifene group exhibited involutionary changes in the repeat mammogram, whereas 25.9% of women in the control group revealed a decrease in breast density in the 12-month examination. The percentages were not significantly different between groups. CONCLUSIONS: Breast density as shown by mammography was stable in a majority of patients and changed in a minority of cases for both tibolone and raloxifene. In most patients, these drugs are not likely to interfere with mammogram interpretation. Larger long-term studies are needed to confirm the impact of prolonged tibolone or raloxifene administration on mammography.

Adult↗

PubMed2006

Strontium ranelate: the first dual acting treatment for postmenopausal osteoporosis.

UNLABELLED: Currently available medications, such as bisphosphonates, selective estrogen receptor modulators, and teriparatides, have shown their ability to reduce vertebral and/or nonvertebral fractures. Questions remain regarding their long-term innocuousness and several studies showed that adhering to currently marketed anti-osteoporotic medications remain sub-optimal. There is, therefore, an urgent need for the development of new effective, safe, and user-friendly medications to optimize the treatment of postmenopausal osteoporosis. The current review was designed to assess, through an extensive literature search, the antifracture efficacy of strontium ranelate on the axial and appendicular skeleton. Two multinational Phase 3 clinical trials have shown its efficacy and safety in the treatment of postmenopausal osteoporosis. In the Spinal Osteoporosis Therapeutic Intervention trial, strontium ranelate (2 g/day) treatment reduced the relative risk of a new vertebral fracture by 41% after 3 years compared with placebo. Data from the Treatment of Peripheral Osteoporosis study showed a 16% reduction in the relative risk of nonvertebral fracture in all patients and a 36% reduction in hip fracture in high-risk patients. Strontium rane-late reduces the risk of all fragility fractures and is well tolerated, which makes it a new first-line alternative in the treatment of postmenopausal osteoporosis. LEVEL OF EVIDENCE: Therapeutic study, Level II (lesser quality randomized controlled trial [eg, < 80% followup, no blinding, or improper randomization]). See the Guidelines for Authors for a complete description of the levels of evidence.

Animals↗

PubMedDate not supplied

Effects of lasofoxifene on bone in surgically postmenopausal cynomolgus monkeys.

OBJECTIVE: The purpose of this study was to evaluate the effects on bone of two doses of the selective estrogen receptor modulator lasofoxifene in surgically postmenopausal cynomolgus monkeys for 24 months. The primary endpoint of this study was biomechanical testing of animals treated for 2 years. DESIGN: The design of the study was a five-group (sham-ovariectomy, ovariectomy, conjugated [0.02 mg/kg], and two doses of lasofoxifene [1.0 and 5.0 mg/kg]), parallel arm design, with the treatments lasting for 24 months. Bone biomarker and estradiol data were collected at baseline and 3, 6, 12, 18, and 24 months after surgery. Vertebral bone mineral density was determined at baseline and every 6 months after ovariectomy. Hip bone density was determined at baseline and 12 and 24 months postovariectomy. Iliac bone biopsies were collected at 7 months, and the second lumbar vertebra and left femur were collected at 24 months after initiation of treatment for histomorphometric examination. The third lumbar vertebra and right femur were tested for mechanical strength after 24 months of treatment. RESULTS: Lasofoxifene and conjugated estrogens prevented ovariectomy-induced increases in serum alkaline phosphatase and CrossLaps and resulted in increased vertebral (all three treatments) and hip (conjugated estrogens and high-dose lasofoxifene only) bone mineral density, although both doses of lasofoxifene exceeded the doses projected to be used in women. In the 7-month iliac biopsy specimens, both doses of lasofoxifene reduced bone turnover rates. These histomorphometric changes were not present in either the vertebral or femoral compartments measured after 24 months of treatment. Lasofoxifene-treated animals did not differ from ovariectomized controls in mechanical strength testing of either the third lumbar vertebra or right femur. CONCLUSIONS: Lasofoxifene prevented ovariectomy-induced increased bone turnover and loss of bone mineral density without having a detrimental effect on bone strength.

Alkaline Phosphatase↗

PubMed2005

Inhibitory effects of idoxifene on hepatic fibrosis in rats.

AIM: To investigate the effects of a tissue-specific selective estrogen receptor modulator, idoxifene, on hepatic fibrosis in rats. METHODS: Hepatic fibrosis was induced by dimethylnitrosamine (DMN) in male rats. The DMN model of hepatic fibrosis and the hepatocytes undergoing oxidative stress were treated with idoxifene respectively. The effect of idoxifene on hepatic fibrosis in the DMN model was examined by immunohistochemistry. Effects of idoxifene on antioxidant enzyme levels of copper, zinc-dependent superoxide dismutase (CuZn-SOD), and cellular glutathione peroxidase (GSHPx) were measured by ELISA. Effects of idoxifene on activation, proliferation, and apoptosis of culture-activated hepatic stellate cells (HSC) were analysed by immunohistochemistry, bromodeoxyuridine (BrdU) uptake, and flow cytometry, respectively. RESULTS: Idoxifene could markedly suppress DMN-induced hepatic fibrosis in male rats. A treatment of 0.4 mg x kg(-1) x d(-1) of idoxifene reduced the protein levels of collagen in the DMN model by 41.19% (P<0.05). Protein level of CuZn-SOD and activitiy of GSHPx in liver treated with DMN plus 0.4 mg/kg/d of idoxifene were 2.65 times (P<0.05) and 2.08 times greater (P<0.05) than that of liver treated with DMN alone respectively. The protein level of CuZn-SOD and activity of GSHPx in cultured rat hepatocytes treated with ferric nitrilotriacetate (FeNTA) plus 1 multiply 10(-7) mol/L of idoxifene were 3.43 times (P<0.05) and 2.52 times (P<0.05) greater than that treated with FeNTA alone. Idoxifene could inhibit HSC activation. Compared with the control, the uptake of BrdU in HSC cultured with 1 multiply 10(-7) mol/L of idoxifene was reduced by 51.87 % (P<0.05), and the number of apoptotic HSCs cultured with 1 multiply 10(-7) mol/L of idoxifene increased by 94.52% (P<0.05). CONCLUSION: Idoxifene showed inhibitory action on hepatic fibrosis in male rats.

Animals↗

PubMed1999

Breast cancer prevention by antiestrogens.

A new era has been entered with the first demonstration that an antiestrogen can prevent breast cancer. In a landmark study tamoxifen was shown to reduce the incidence of breast cancer by approximately 50%. The reduction was observed in pre- and postmenopausal women at increased risk of breast cancer. Invasive cancers were reduced, the reduction being in the estrogen receptor-positive cancers. No preventive effect was observed for estrogen receptor-negative tumors. In situ cancers were also significantly reduced. A collateral benefit was a significant reduction in fractures due to osteoporosis. Adverse effects included a very small increase in the incidence of endometrial cancer, cataracts, and stroke. The benefits appear to outweigh the risks for those at high risk. Preliminary studies of a new selective estrogen receptor modulator (SERM 2), raloxifene, developed for the prevention of osteoporosis, have shown that the breast cancer rate was reduced by more than 50% without any concomitant increase in endometrial cancer. The search for a SERM 3, and beyond, may lead to the development of drugs that have the beneficial effects of estrogen while preventing breast cancer and osteoporosis.

Antineoplastic Agents, Hormonal↗

PubMed2001

An in vivo/in vitro model to assess endocrine disrupting activity of xenoestrogens in uterine leiomyoma.

Xenoestrogens with endocrine disrupting activity have been associated with the dysregulation of reproductive function and promotion of malignancies in experimental animals and human populations. The high incidence of uterine leiomyomas, a benign estrogen-responsive neoplasm of the uterine myometrium, calls into question the potential influence of xenoestrogens in the pathogenesis of these tumors. An in vivo/in vitro animal model, the Eker rat, that can be used to assess the estrogen-like agonist activity of potential endocrine disruptors in the uterine myometrium is discussed. Using this model, several in vitro assays are developed that demonstrate that compounds from three major classes of xenoestrogens can mimic the effect of estrogen on leiomyoma cells and act as estrogen receptor (ER) agonists: phytoestrogens, organochlorine pesticides and pharmacologic agents. These compounds can stimulate transcription via the ER and upregulate the expression of an estrogen-responsive gene in uterine leiomyoma cells. The use of these in vitro assays has also advanced our ability to predict the agonist activity of potential therapeutic agents in the uterine myometrium. Selective estrogen receptor modulators (SERMs), while able to act as agonists in some tissues such as the bone and uterine endometrium, act as antagonists in vivo in the uterine myometrium and in our in vitro assays. This antagonist activity in the uterine myometrium suggests that SERMs may be useful in the treatment of uterine leiomyoma.

Animals↗

PubMed2002

Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance.

Raloxifene, a selective estrogen receptor modulator used for the treatment of osteoporosis, undergoes extensive conjugation to the 6-beta- and 4'-beta-glucuronides in vivo. This paper investigated raloxifene glucuronidation by human liver and intestinal microsomes and identified the responsible UDP-glucuronosyltransferases (UGTs). UGT1A1 and 1A8 were found to catalyze the formation of both the 6-beta- and 4'-beta-glucuronides, whereas UGT1A10 formed only the 4'-beta-glucuronide. Expressed UGT1A8 catalyzed 6-beta-glucuronidation with an apparent K(m) of 7.9 microM and a V(max) of 0.61 nmol/min/mg of protein and 4'-beta-glucuronidation with an apparent K(m) of 59 microM and a V(max) of 2.0 nmol/min/mg. Kinetic parameters for raloxifene glucuronidation by expressed UGT1A1 could not be determined due to limited substrate solubility. Based on rates of raloxifene glucuronidation and known extrahepatic expression, UGT1A8 and 1A10 appear to be primary contributors to raloxifene glucuronidation in human jejunum microsomes. For human liver microsomes, the variability of 6-beta- and 4'-beta-glucuronide formation was 3- and 4-fold, respectively. Correlation analyses revealed that UGT1A1 was responsible for 6-beta- but not 4'-beta-glucuronidation in liver. Treatment of expressed UGTs with alamethicin resulted in minor increases in enzyme activity, whereas in human intestinal microsomes, maximal increases of 8-fold for the 6-glucuronide and 9-fold for the 4'-glucuronide were observed. Intrinsic clearance values in intestinal microsomes were 17 microl/min/mg for the 6-glucuronide and 95 microl/min/mg for the 4'-isomer. The corresponding values for liver microsomes were significantly lower, indicating that intestinal glucuronidation may be a significant contributor to the presystemic clearance of raloxifene in vivo.

Alamethicin↗

PubMed2003

Tamoxifen is a potent inhibitor of cholesterol esterification and prevents the formation of foam cells.

Tamoxifen is a selective estrogen receptor modulator (SERM) used for the treatment and prevention of breast cancer. Tamoxifen has been reported to protect against the progression of coronary artery diseases in human and different atherosclerosis animal models by blocking the appearance of the atheromatous plaque. However, the molecular mechanism of this effect remains unknown. Acyl-CoA:cholesterol acyl transferase (ACAT) catalyzes the biosynthesis of cholesteryl esters, which are the major lipids found in the atheromatous plaque. In this paper we have tested whether ACAT might be inhibited by tamoxifen. We show, using molecular modeling, that tamoxifen displays three-dimensional structural homology with Sah 58-035 (3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide), a prototypical inhibitor of ACAT. We report that tamoxifen inhibits ACAT in a concentration-dependent manner on rat liver microsomal extract. We show that the presence on estrogen receptor ligands of a backbone isosteric to the diphenyl ethane backbone of Sah 58-035 constitutes a pharmacophore for ACAT inhibition. More importantly, tamoxifen was able to inhibit ACAT on intact macrophages stimulated with acetylated low-density lipoproteins and blocked the formation of foam cells, a step that precedes the formation of the atheromatous plaque. This work constitutes the first evidence that tamoxifen is an inhibitor of ACAT and foam cell formation at therapeutic doses and that this may account for its atheroprotective action.

Animals↗

PubMed2005

Expression profiling of rat femur revealed suppression of bone formation genes by treatment with alendronate and estrogen but not raloxifene.

The pharmacological preservation of bone in the ovariectomized rat by estrogen, selective estrogen receptor modulators (SERMs), and bisphosphonates has been well described. However, comprehensive molecular analysis of the effects of these pharmacologically diverse antiresorptive agents on gene expression in bone has not been performed. This study used DNA microarrays to analyze RNA from the proximal femur metaphysis of sham and ovariectomized vehicle-treated rats, and ovariectomized rats treated for 35 days with maximally efficacious doses of 17-alpha ethinyl estradiol, the benzothiophene SERM, raloxifene, the benzopyran SERM, (S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-7-ol (EM652), and the aminobisphosphonate, alendronate. Ovariectomy resulted in 644 significant probe set changes relative to sham control rats (p < 0.05), whereas E2, raloxifene, EM652, and alendronate regulated 613, 765, 652, and 737 probe sets, respectively, relative to ovariectomized control rats. An intersection of these data sets yielded 334 unique genes that were altered after ovariectomy and additionally changed by one or more antiresorptive treatment. Clustering analysis showed that the transcript profile was distinctly different for each pharmaceutical agent and that raloxifene maintained more genes at sham levels than any other treatment. In addition, E2 and alendronate suppressed a cluster of genes associated with bone formation activity below that of sham, whereas raloxifene had little effect on these genes. These data indicate stronger suppressive effects of E2 and alendronate on bone formation activity and that ovariectomy plus raloxifene resembles sham more closely than ovariectomized animals treated with E2, EM652, or alendronate.

Alendronate↗