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Biomedical subjects

V C Jordan

Publications and source records attributed to V C Jordan.

At least 325 records · Page 18Linked to original sources
PubMed1980

Modulation of rat uterine steroid hormone receptors by estrogen and antiestrogen.

The effect of sc injections (25 microgram) of estradiol benzoate, monohydroxytamoxifen [1-(4 beta-dimethylaminoethoxyphenyl)1-(4-hydroxyphenyl)-2-phenylbut-1-ene] and tamoxifen [trans-1-(4 beta-dimethylaminoethoxyphenyl)1,2-diphenylbut-1-ene] every 12 h on uterine wet weight, DNA, and cytoplasmic estrogen and progesterone receptor levels has been studied in the immature rat for up to 90 h. Estradiol benzoate produced a 4-fold rise in uterine wet weight, with a doubling of uterine DNA within 48 h. Tamoxifen and monohydroxytamoxifen doubled uterine weight, with a small rise in uterine DNA. Cytoplasmic estrogen receptor levels were reduced within 24 h by all treatments. Estradiol benzoate and monohydroxytamoxifen produced a maximal rise in nuclear estrogen receptor levels within 8 h, followed by a rapid decline to control levels within 80 h. Tamoxifen produced a slower rise in nuclear estrogen receptor levels and never reached the levels achieved by estradiol or monohydroxytamoxifen. The level of nuclear tamoxifen-estrogen receptor complexes slowly decreased with time. In each case, the cytoplasmic progesterone receptor levels increased as nuclear estrogen receptor levels decreased. Cycloheximide (5 microgram/2 h for 8 h before and 20 h after the first estrogen or antiestrogen injection) was used to determine the effect of protein synthesis inhibition on the hormone receptor profiles. Progesterone receptor synthesis was inhibited by cycloheximide. Cycloheximide did not affect translocation, but produced a rapid decrease in nuclear estrogen receptor levels. The results suggest that without the continual translocation of estrogen receptors from the cytoplasm, the antiestrogen-estrogen receptor levels in the nuclear compartment decrease because of destruction or processing. The nuclear antiestrogen-estrogen receptor pool is therefore not static but dynamic. High affinity ligand-estrogen receptor complexes are readily processed in the nucleus to effect progesterone receptor synthesis in the cytoplasm; however, this series of biochemical reactions is only secondary to the fundamental events essential for cell division. After an initial increase in cytoplasmic steroid receptor synthesis by estrogen or antiestrogen, there is a gradual reduction in total cytoplasmic and nuclear estrogen receptor complexes in response to continual nuclear stimulation. This reduction, in turn, reduces progesterone receptor synthesis.

Animals↗
PubMed1980

Subcellular effects of monohydroxytamoxifen in the rat uterus: steroid receptors and mitosis.

The administration of either monohydroxytamoxifen (25 micrograms) or oestradiol benzoate (25 micrograms) to immature rats resulted in similar depletion of the cytoplasmic oestrogen-receptor pool, with a transient (approx. 48 h) increase in nuclear oestrogen-receptor levels. Oestradiol benzoate increased uterine wet weight with a corresponding increase in uterine cytoplasmic progesterone-receptor levels, DNA content and cell division at 48 h. In contrast, monohydroxytamoxifen produced only a partial increase in uterine wet weight. Although the increase in concentration of uterine progesterone receptors (per mg DNA) by monohydroxytamoxifen was comparable to that produced by oestradiol benzoate, the nuclear antioestrogen-oestrogen-receptor complexes were unable to stimulate a large rise in whole uterine DNA content and cell division. Examination of stromal and epithelial mitotic activity 48 h after administration of 0.25, 2.5 and 25 micrograms oestradiol benzoate, monohydroxytamoxifen or tamoxifen showed that the inability of antioestrogens to stimulate oestrogen-like mitotic activity was not related to the dose of antioestrogen that was administered. It is suggested that the inability of the antioestrogen-oestrogen-receptor complexes to initiate the nuclear events which lead to cell division should be exploited in the investigation of the nuclear mechanism of oestrogen action. The high potency of monohydroxytamoxifen and its inherent biological activity, in that it is not metabolically activated before exerting its effects, provide clear advantages for its future use as a pharmacological probe.

Animals↗
PubMed1979

Inhibition of cell division and stimulation of progesterone receptor synthesis in rat oestrogen target tissues by non-steroidal antioestrogens.

Recent studies from this laboratory have demonstrated oestradiol-oestrogen receptors associated with the nuclear compartment of the rat uterine cell will initiate protein synthesis, as evidenced by a rise in progesterone receptor concentrations, and cell division whereas the anti-oestrogen - oestrogen receptor complex causes protein synthesis and cellular hypertrophy rather than hyperplasia. It is probable that this separation of biological activities resides in the intrinsic activity of the respective receptor complexes. We have demonstrated that caution should be exercised in the interpretation of low affinity ligand-hormone receptor interactions undertaken in vitro. Simple tests for ligand specificity for a binding protein are clearly insufficient evidence to characterise a hormone receptor complex using a conventional 15 hr technique of sucrose density gradient analysis. Oestrogens and anti-oestrogens do not seem to disrupt the subunit integrity of the cytoplasmic oestrogen receptor and it appears likely that the ligand plays a fundamental role in confering the correct biological properties to the hormone receptor complex.

Animals↗
PubMed1979

The binding of [3H]-oestradiol-17 beta in the immature rat uterus during the sequential administration of non-steroidal anti-oestrogens.

1 The binding of [(3)H]-oestradiol-17beta (0.08 mug) in the uterus, vagina, liver and heart of immature female rats has been studied in vivo and the effect of daily administrations of the non-steroidal anti-oestrogens, tamoxifen and monohydroxytamoxifen, on the 2 h accumulation of [(3)H]-oestradiol-17beta in the uterus has been determined.2 Doses of tamoxifen (8 mug daily) or monohydroxytamoxifen (1.28 mug daily), which have previously been found to antagonize completely the uterotrophic activity of oestradiol-17beta (0.08 mug daily), did not significantly reduce the total uterine binding of 0.08 mug [(3)H]-oestradiol-17beta administered on day 4 of a 3-day uterine weight test.3 The simultaneous administration of tamoxifen (8 mug) or monohydroxytamoxifen (1.28 mug) with [(3)H]-oestradiol-17beta (0.08 mug) on day 3 of a uterine weight test did not significantly reduce the total uterine binding of oestradiol-17beta. The binding of [(3)H]-oestradiol-17beta was reduced if monohydroxytamoxifen or tamoxifen was administered 4 h before the oestradiol.4 Tamoxifen (8 mug daily) or monohydroxytamoxifen (1.28 mug daily) did not prevent the translocation of [(3)H]-oestradiol (0.08 mug) to the uterine cell nucleus on day 3 of a 3-day uterine weight test.5 The measurement of total nuclear oestrogen receptors by an exchange assay technique demonstrated a higher concentration of oestrogen receptors in anti-oestrogen-treated animals compared with controls.6 Since the administration of anti-oestrogenic doses of non-steroidal anti-oestrogens during a 3-day uterine weight test did not inhibit the total binding of oestradiol in the uterus, or affect the translocation of the steroid to the nucleus, the mechanism of action of non-steroidal anti-oestrogens over the range of the partial agonist dose-response curve must involve an interaction, or competition of oestradiol-17beta- and anti-oestrogen-oestrogen receptor complexes for sites within the nucleus.

Animals↗
PubMed1978

Dose-related effects of non-steroidal antioestrogens nad oestrogens on the measurement of cytoplasmic oestrogen receptors in the rat and mouse uterus.

The dose-related effects of non-steroidal antioestrogens and oestrogens on the measurement of cytoplasmic oestrogen receptors in the rat uterus have been determined. The simultaneous administration of tamoxifen or monohydroxytamoxifen and oestradiol on three consecutive days resulted in dose-dependent decreases in both the wet weight of the uterus and the number of available cytoplasmic oestrogen receptors. The oestrogenic triphenylethylenes ICI 47 699 and ICI 3188 both produced dose-dependent decreases in the number of available cytoplasmic oestrogen receptors. Increasing doses of ICI 47 699 resulted in increasing concentrations of oestrogen receptors within the nucleus. The effects of tamoxifen and oestradiol-17 beta were compared in the ovariectomized mouse; replenishment of uterine oestrogen receptors was less evident in tamoxifen-treated animals than in animals receiving oestradiol, although increases in uterine weight were similar. A single large dose of tamoxifen (50 microgram) produced a prolonged depletion of cytoplasmic oestrogen receptors whilst stimulating rises in uterine weight and DNA and protein content. The results demonstrate that the depletion of the uterine cytoplasmic oestrogen receptor pool is a function of the dose administered for any compound with the ability to translocate oestrogen receptors to the nucleus and as such is not an exclusive characteristic of non-steroidal antioestrogens.

Animals↗