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Studies on the mechanism of action of the nonsteroidal anti estrogen tamoxifen ici 46474 in the rat


, : Studies on the mechanism of action of the nonsteroidal anti estrogen tamoxifen ici 46474 in the rat. Molecular and Cellular Endocrinology 7(2): 177-192

The interaction of tamoxifen [I.C.I. 46,474] with the rat uterine estrogen receptor protein was investigated. Administration of tamoxifen to immature female rats produced a dose-dependent decrease in cytoplasmic estrogen receptor concentrations and exchange methods were used to demonstrate a rise in nuclear estrogen receptor concentrations. In immature rat uterine weight tests tamoxifen produced a partial uterotrophic response over a dose range of 0.5-8.0 .mu.g/day and the same doses, administered simultaneously with estradiol, produced a dose-related inhibition of estrogen-stimulated uterine wet weight increases and uterine DNA content. Measurement of cytoplasmic estrogen receptor concentrations during a uterine weight test demonstrated that 4 .mu.g tamoxifen produced significant antiuterotrophic effects without a complete depletion of cytoplasmic estrogen receptors. A single administration of tamoxifen (4 .mu.g) produced a slow but prolonged rise in uterine wet weight associated with a slow decrease in cytoplasmic estrogen receptors and a prolonged rise in estrogen receptor levels in the nucleus. By 24 h cytoplasmic estrogen receptor concentrations had returned to control levels. After a single dose of estradiol (0.08 .mu.g) there was a rapid decrease in cytoplasmic estrogen receptors associated with a rapid rise in uterine wet weight but only a small rise in nuclear estrogen receptor concentrations. In estradiol-treated animals neither rises in uterine weight nor nuclear estrogen receptor concentrations were maintained after 24 h. Estrogen receptors which were translocated to the nucleus after a large dose of estradiol (0.9 .mu.g) were in the main salt (0.4 M KCl) extractable, although a small but significant proportion were salt resistant. Estrogen receptors translocated after tamoxifen were completely salt extractable. The change in the properties of the estrogen receptor is probably responsible for the partial agonistic effects of tamoxifen. Since tamoxifen does not have to deny estrogen binding completely to produce antiestrogenic effects in the uterus, a competition between tamoxifen-estrogen receptor complexes and estradiol-estrogen receptor complexes for nuclear acceptor sites may be the primary antiestrogenic mechanism.

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PMID: 863099


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