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Effects of CP336,156, a New, Nonsteroidal Estrogen Agonist/Antagonist, on Bone, Serum Cholesterol, Uterus, and Body Composition in Rat Models

Effects of CP336,156, a New, Nonsteroidal Estrogen Agonist/Antagonist, on Bone, Serum Cholesterol, Uterus, and Body Composition in Rat Models,HUA ZHU

Effects of CP336,156, a New, Nonsteroidal Estrogen Agonist/Antagonist, on Bone, Serum Cholesterol, Uterus, and Body Composition in Rat Models   (Citations: 25)
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HUA ZHU KE, VISHWAS M. PARALKAR, WILLIAM A. GRASSER, D. TODD CRAWFORD, HONG QI, HOLLIS A. SIMMONS, CHRISTINE M. PIRIE, KRISTIN L. CHIDSEY-FRINK, THOMAS A. OWEN, STEVEN L. SMOCK, HONG KA CHEN, WEBSTER S. S. JEEhttp://academic.research.microsoft.com/io.ashx?type=5&id=6656646&selfId1=0&selfId2=0&maxNumber=12&query=
We have discovered a new, nonsteroidal, potent estrogen agonist/ antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-a with a half-inhibition con- centration of 1.5 nM, which is similar to that seen with estradiol (4.8 nM). When given orally to immature (3-week-old) female Sprague- Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 mg/kgzday, unlike 17a-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (po) with CP-336,156 at 10 or 100 mg/kgzday for 28 days. We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX- induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 mg/kgzday after 4 weeks. At these doses, CP-336,156 completely prevented OVX-in- duced bone loss and inhibited the increased bone turnover associated with estrogen deficiency in lumbar vertebrae, proximal tibiae, and distal femora. Similar to estrogen, CP-336,156 induced apoptosis and p53 expression with a concomitant decrease in the number of tartrate- resistant acid phosphatase-positive multinuclear cells in rat bone marrow cell cultures in vitro, suggesting that the induction of apo- ptosis may be a mechanism for the estrogenic activities of CP-336,156 in bone. In summary, CP-336,156 is a new, orally active, nonsteroidal, potent estrogen agonist/antagonist that has similar effects in bone as estradiol but without the uterine-stimulating effects associated with estradiol in rats. (Endocrinology 139: 2068 -2076, 1998)
Published in 2010.
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    • ...5‐7). Several lines of recent evidence suggest a potential role for the ER in the determination of BMI: 1) a subtype of ER may have a role in ER-mediated responses in human adipose tissue (8); 2) a potent estrogen agonist/antagonist decreases fat body mass in aged female rats (9); 3) a selective ER modulator increases body mass (10); 4) the progesterone/estrogen receptor ratio correlates positively with BMI, which may reflect a correlation ...

    HONG-WEN DENGet al. Association of Estrogen Receptor-a Genotypes with Body Mass Index in N...

    • ... which showed that p53 expression induced by an oestrogen agonist/antagonist was localised in apoptotic cells in rat bone marrow....

    R Okazakiet al. Trabecular bone mass and bone formation are preserved after limb immob...

    • ...Prior to the initiation of clinical trials, we performed a series of in vitro and in vivo preclinical studies to characterize the effects of LAS on bone, serum lipids, breast and uterine tissues (27-30)...
    • ...The efficacy of lasofoxifene (LAS) in preventing bone loss was first tested using the OVX rat model (27)...
    • ...the induction of apoptosis may be one of the mechanisms for the estrogen agonistic activities of LAS in bone (27)...
    • ...Using the OVX rat model, we found that LAS significantly reduced total serum cholesterol as compared with both the sham and OVX controls, as shown in Figure 6A (27)...
    • ...As shown in Figure 7A, LAS at doses equal to or greater than 10 pg/kg/day slightly but significantly increased uterine wet weight with no dose-dependent response for up to 1000 pg/kg/day as compared with vehicle-treated OVX rats (27)...
    • ...The uterine effects of I_AS were further characterized in the immature female rat model and in aged female rat (27)...
    • ...Sixty days post-surgery, the OVX rats were treated with either bovine PTH-(1-34) at 40 pg/kg by daily s.c...
    • ...Sixty days post-OVX, the rats were treated with either bovine PTH-(1-34) at 40 pg/kg by daily s.c...
    • ...LAS: lasofoxifene at 100 mg/kg/day, oral; PTH: bovine parathoroid hormone-(1-34) at 40 mg/kg/day, s.c...

    H. Z. Keet al. Lasofoxifene (CP336,156), a novel selective estrogen receptor modulato...

    • ...Preclinical studies indicate that it prevents lumbar vertebral bone loss in the OVX rat model, with greatly enhanced potency relative to raloxifene (11, 12)...

    Leonard A. Cohenet al. LAS, a Novel Selective Estrogen Receptor Modulator with Chemopreventiv...

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