David E. Magee

Environmental estrogens : Effects on cholesterol lowering and bone in the ovariectomized rat

Representative non-steroidal estrogens, from common environmental sources such as plants, pesticides, surfactants, plastics, and animal health products, demonstrated an ability to lower serum cholesterol and prevent bone loss. Specifically, select environmental estrogens (coumestrol, genistein, methoxychlor, bisphenol A, and zeranol) effectively lowered total serum cholesterol in an estrogen-dependent animal model, the ovariectomized rat. Of these entities, coumestrol, methoxychlor, and zeranol prevented ovariectomy-induced bone loss. In an in vitro environment, these compounds competed with 17beta-estradiol for estrogen receptor binding and stimulated cell proliferation in a human breast cancer cell line (MCF-7). In addition to their well-documented effects on reproductive tissue, various environmental estrogens can dramatically affect non-reproductive parameters such as cholesterol lowering and bone metabolism.

Raloxifene is a Tissue‐Selective Agonist/Antagonist That Functions through the Estrogen Receptor

Raloxifene (LY 139481), previously called keoxifene, is a benzothiophene derivative that binds to the estrogen receptor (ER) with high affinity (kd = 0.54-0.11 nM).’ This compound has tissue-specific activity, acting as an antiestrogen in breast and uterus, but functioning as an estrogen agonist in bone and on lipid metabolism. The molecular mechanisms of this tissue specificity are still under investigation, but preliminary evidence indicates that raloxifene-ER complexes associate with unique response elements, thus indicating that multiple transcriptional pathways may mediate these e f f e ~ t s . ~ ’ ~

Effect of Weight Manipulation on Bone Loss Due to Ovariectomy and the Protective Effects of Estrogen in the Rat

SummaryWhile characterizing the effects of estrogen on an ovariectomized (OVX) rat model of bone loss, we examined several weight-matching regimens e.g.,ad libitum (feed bins continually full), weight matched (rate of weight gain for OVX and Sham-OVX groups was equalized), and weight restricted (weight gain rates for all groups were equalized to that of estrogen-treated OVX rats) for possible effects. Bone loss following ovariectomy is primarily the result of an increase in bone resorption and is extremely sensitive to the effects of estrogens. Thus, in all of our analyses, treatment with 170-estradiol served as a positive control for the prevention of bone loss. Each weight-matching study had three groups: control (Sham-OVX), OVX, and OVX + 170 estradiol (0.1 mg/kg/day), and lasted for either 2, 4, or 6 weeks. Throughout the study, each Sprague Dawley rat was weighed every other day, and following sacrifice, a femur was removed for bone mineral density (BMD) analysis at the distal metaphysis by single photon absorptiometry. Following 2 weeks of dietary modifications, no significant differences were detected in BMD among thead lib or weight matched groups. However, an estradiol-preventable reduction in BMD in restricted OVX rats was detected at 2 weeks postovariectomy. Additionally, OVX rats in all three dietary regimens displayed an estrogen-preventable reduction in proximal femur BMD at 4 and 6 weeks postovariectomy. These results indicate that a 4-week rat ovariectomized model of bone loss, under conditions of ad libitum feeding, shows great potential for pharmacologic manipulation.

Benzopyran selective estrogen receptor modulators (SERMs): Pharmacological effects and structural correlation with raloxifene

Abstract Several 2,3-diarylbenzopyrans have been evaluated in an ovariectomized rat model and found to exhibit tissue selective estrogen agonist activity on bone and serum lipid parameters. A structural model that accounts for the pharmacological similarity of these benzopyrans and the benzothiophene SERM, raloxifene, is proposed.

Synthesis and pharmacology of 2-alkyl raloxifene analogs

Abstract A series of 2-alkyl and 2-cycloalkyl raloxifene analogs have been prepared and evaluated in both in vitro and in vivo models of estrogen/antiestrogen activity. In particular, the 2-cyclohexyl analogs show promise as potent selective estrogen-receptor modulators (SERMs).

Serotonin-induced paw edema in the rat: Pharmacological profile

1. Serotonin (5-HT) induced a linear increase in paw weight in rats within 1 hr of an intraplantar injection (50 microliters vol) over a concentration range of 0.005-0.2 mg/ml. At the 0.2 mg/ml concentration, a 16-fold increase in paw weight was observed as compared to saline-injected controls. 2. Serotonin antagonists, such as LY53857, were the most effective antagonists of 5-HT induced paw swelling, producing near complete antagonism and an approximate ED50 of 0.1 mg/kg. A mixed 5-HT/histamine antagonist, cyproheptadine, also produced a nearly complete inhibition of the 5-HT response with an approximate ED50 of 1.3 mg/kg. 3. Dopamine agonists (pergolide, quinpirole), yohimbine, dexamethasone and nifedipine also produced a significant degree of antagonism of the 5-HT response. 4. Clonidine, prazocin, chlorpheniramine, cimetidine, various dopamine antagonists, imipramine, cyclosporine A, piroxicam and superoxide dismutase were all ineffective at altering the paw swelling response to 5-HT.

Conversion of the phytoestrogen coumestrol into a selective estrogen receptor modulator (SERM) by attachment of an amine-containing sidechain

Abstract The naturally occurring estrogen mimetic coumestrol has been shown to stimulate proliferation of MCF-7 mammary tumor cells and to cause uterotrophic effects in ovariectomized (OVX) rats. Attachment of a basic amine-containing sidechain to C-6 of coumestrol converts this estrogen agonist into an antagonist in breast and uterine tissue, while maintaining its estrogen-like activity as a hypocholesterolemic agent.