Sömjen D, Waisman A, Kaye A M
Sackler Faculty of Medicine, Tel-Aviv University, Israel.
J Steroid Biochem Mol Biol. 1996 Dec;59(5-6):389-96. doi: 10.1016/s0960-0760(96)00135-5.
We have compared the cell and tissue selective estrogenic and antiestrogenic activities of tamoxifen, raloxifene, ICI 164,384 and a permanently ionized derivative of tamoxifen--tamoxifen methiodide (TMI). This non-steroidal antiestrogen has limited ability to cross the blood brain barrier and is therefore less likely to cause the central nervous system disturbances caused by tamoxifen. We have used the stimulation of the specific activity of the "estrogen induced protein", creatine kinase BB, as a response marker in bone, cartilage, uterine and adipose cells and in rat skeletal tissues, uterus and mesometrial adipose tissue. In vitro, TMI, tamoxifen and raloxifene mimicked the agonistic action of 17beta-estradiol in ROS 17/2.8 rat osteogenic osteosarcoma, female calvaria, and SaOS2 human osteoblast cells. In Ishikawa endometrial cancer cells, tamoxifen showed reduced agonistic effects and raloxifene showed no stimulation. However, as antagonists, tamoxifen and raloxifene were equally effective in Ishikawa or SaOS2 cells. In immature rats, all four of the antiestrogens inhibited estrogen action in diaphysis, epiphysis, uterus and mesometrial adipose tissue; when administered alone, tamoxifen stimulated creatine kinase (CK) specific activity in all these tissues. Raloxifene and TMI, however, stimulated only the skeletal tissues and had no stimulatory effect in the uterus or mesometrial fat, and the pure antiestrogen ICI 164,384 showed no stimulatory effect in any of the tissues. The simultaneous injection of estrogen, plus an antiestrogen which acted as an agonist, resulted in lower CK activity than after injection of either agent alone. These differential effects, in vivo and in vitro, may point the way to a wider therapeutic choice of an appropriate antiestrogen which, although antagonizing E2 action in mammary cancer, can still protect against osteoporosis and cardiovascular disease and not stimulate the uterus with its attendant undesirable changes, or interfere with the beneficial action of E2 in the brain.
我们比较了他莫昔芬、雷洛昔芬、ICI 164,384以及他莫昔芬的一种永久离子化衍生物——他莫昔芬甲碘化物（TMI）的细胞和组织选择性雌激素活性及抗雌激素活性。这种非甾体类抗雌激素穿过血脑屏障的能力有限，因此不太可能引发他莫昔芬所致的中枢神经系统紊乱。我们采用刺激“雌激素诱导蛋白”（肌酸激酶BB）的比活性作为骨、软骨、子宫及脂肪细胞以及大鼠骨骼组织、子宫和子宫系膜脂肪组织中的反应标志物。在体外，TMI、他莫昔芬和雷洛昔芬在ROS 17/2.8大鼠成骨骨肉瘤细胞、雌性颅骨及SaOS2人成骨细胞中模拟了17β-雌二醇的激动作用。在石川子宫内膜癌细胞中，他莫昔芬的激动作用减弱，而雷洛昔芬无刺激作用。然而，作为拮抗剂，他莫昔芬和雷洛昔芬在石川或SaOS2细胞中效果相当。在未成熟大鼠中，所有这四种抗雌激素均抑制骨干、骨骺、子宫和子宫系膜脂肪组织中的雌激素作用；单独给药时，他莫昔芬刺激所有这些组织中的肌酸激酶（CK）比活性。然而，雷洛昔芬和TMI仅刺激骨骼组织，对子宫或子宫系膜脂肪无刺激作用，而纯抗雌激素ICI 164,384在任何组织中均无刺激作用。同时注射雌激素及作为激动剂的抗雌激素后，CK活性低于单独注射任何一种药物后的活性。这些体内和体外的差异效应可能为更广泛地选择合适的抗雌激素提供方向，这种抗雌激素虽然在乳腺癌中拮抗E2作用，但仍可预防骨质疏松症和心血管疾病，且不会刺激子宫产生不良变化，也不会干扰E2在大脑中的有益作用。
