Effect of Antiestrogens on Uterine Estradiol Receptors

Rochefort, Henri; Lignon, F; Capony, Françoise

doi:10.1159/000301744

Cited by 27 publications

(6 citation statements)

References 26 publications

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“…The anti-oestrogen nafoxidine hydrochloride (1 -{2 -[p -(3,4 -dihydro -6 -methoxy -2 -phenyl -1naphthyl)phenoxy]ethyl}pyrrolidine hydrochloride; Upjohn 11100A) is a diphenyldihydronaphthalene derivative which has been widely used in mammalian systems (Jensen & DeSombre, 1973). It binds both the cytoplasmic and nuclear forms of oestradiol receptor in rat uterus (Rochefort et al, 1972a). It exhibits both agonistic and antagonistic effects in rat uterus, and recent work suggests that a site of the antagonistic action is in the blockage or delay in replenishment of the cytoplasmic oestrogen receptor (Clark et al, 1974;Katzenellenbogen & Ferguson, 1975;Capony & Rochefort, 1975).…”

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confidence: 99%

Interaction of the anti-oestrogen, nafoxidine hydrochloride, with the soluble nuclear oestradiol-binding protein in chick liver

Lazier¹,

Alford²

1977

Biochemical Journal

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Nafoxidine hydrochloride (Upjohn, 11100A)injected with oestradiol into immature chicks inhibits the hormone-induced increase in [3H]oestradiol-binding activity in salt extracts of liver nuclei as well as the subsequent production by liver of egg-yolk phosphoprotein. Substantial inhibition of both oestradiol-induced responses is seen when nafoxidine is given in a dose approximately equimolar with that of oestradiol. In vitro nafoxidine competitively inhibits binding of [3H]oestradiol in nuclear extracts. The Ki for the inhibition is 43 nM, which indicates an affinity of nafoxidine for the binding protein about 4% of that of oestradiol. The inhibitory action of nafoxidine in vivo thus is more potent than the relative binding affinity determined in vitro might indicate. One possible explanation is that the primary site of nafoxidine action is at a point proximal to nuclear receptor interaction. Nafoxidine injected alone into the chick does not induce phosphoprotein synthesis, but it does increase [3H]oestradiol-binding activity in extracts of liver nuclei to a limited extent. No differences in the properties of the oestradiol-binding activity in extracts from nafoxidine-treated chicks or from oestradiol-treated chicks were detected. Chick liver cytosol does not contain detectable high-affinity oestradiol-binding activity. A low-affinity oestradiol-binding component with a sedimentation coefficient of 3.5S was found, but it was unaffected by treatment of chicks with earlier nafoxidine or oestradiol. The results suggest a difference in the mechanism of oestradiol action in the chick liver and in the widely studied rat uterus, on which the usual model for oestradiol action is largely based.

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confidence: 99%

Interaction of the anti-oestrogen, nafoxidine hydrochloride, with the soluble nuclear oestradiol-binding protein in chick liver

Lazier¹,

Alford²

1977

Biochemical Journal

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“…These puzzling findings plus the observation that doses of the clomiphene isomers that evoked submaximal responses also main tained the UBF near the highest level reached at those doses for an aver age period of 4-5 h (table I) suggest that recirculation is not the only mechanism responsible for the prolonged effects seen after cis-or transclomiphene injection. One possible explanation is that if the clomiphene isomers produce UBF increases through the estrogen receptor system, as they presumably do [12], then they are capable of prolonged stimulation of these receptors as compared to estradiol-17/?, perhaps due to conformatio nal differences. Another possibility is that stimulation by estradiol-17/?…”

Section: Discussionmentioning

confidence: 99%

Effect of Cis- and Trans-Clomiphene on the Uterine Blood Flow of Oophorectomized Ewes

Jg¹,

Fc²

1976

Gynecol Obstet Invest

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Changes in the left uterine artery blood flow (UBF) after intraarterial administration of estradiol-17β and cis- and trans-clomiphene citrate to conscious, oophorectomized ewes were monitored by chronically implanted electromagnetic flow probes. Cis-clomiphene produced UBF increases comparable to or greater than those produced by estradiol-17β but at dose levels 20 times greater. Comparison of UBF response curves for cis-clomiphene with those for estradiol-17β showed a delayed onset of initial vasodilation and a delayed peak response. The duration of uterine vasodilation produced by cis-clomiphene was dose-dependent and exceeded that produced by estradiol-17β. Similar responses were observed with trans-clomiphene but at dose levels at least 1,000 times those of estradiol-17β. The characteristics of clomiphene-induced UBF responses that differed from those after estradiol-17β may reflect differences in estrogen receptor activation between the compounds.

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“…Lamb or calf uteri were used either within an hour following slaughter or after freezing in liquid N, and storage at -80 "C. Cytosol was prepared in Tris/EDTA buffer (10 mM Tris/HCl, 1.5 mM EDTA, pH 7.4) as described previously [2]. …”

Section: Methodsmentioning

confidence: 99%

“…The reason for the low biological efficiency of antiestrogens when bound to the estrogen receptor (ER) is, however, not clear. It is known that antiestrogens are able to induce nuclear translocation of estrogen receptor [2,3] and some, but not all, estrogen-specific responses [4]. It is therefore likely that the reason for their weak estrogenic activity is due to an alteration of the ER interaction with chromatin acceptor sites [5].…”

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confidence: 99%

Estrogen-Receptor-DNA Interaction

Evans

Baskevitch

Rochefort

2005

European Journal of Biochemistry

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We have compared the interaction of the cytosol estrogen receptor with calf thymus DNA after its binding to [3H]estradiol or 4-hydroxy['H]tamoxifen, a high-affinity antiestrogen, in an attempt to find a difference in the nature of these two complexes. The activation of the receptor and its binding to DNA were simultaneously obtained during an 18-h incubation at 0 "C. The binding of a constant concentration of estrogen receptor to increasing concentrations of adsorbed DNA was examined. Scatchard representation of the data showed that the antiestrogen -receptor complex has a twofold lower affinity for DNA than the estradiol-receptor complex, while the proportion ofreceptor able to bind DNA was the same whether bound to estradiol or antiestrogen.Similar results were obtained by using soluble DNA and separation of the unbound and DNA-bound receptor on sucrose gradients.These results indicate that the estrogen receptor binds in v i m to non-specific double-stranded DNA with a lower affinity when it has been activated by an antiestrogen than when activated by estradiol.Antiestrogens are estrogen analogues which prevent estrogen action at the target tissue level by competitive inhibition of the binding ofestrogen to its receptors [l]. The reason for the low biological efficiency of antiestrogens when bound to the estrogen receptor (ER) is, however, not clear. It is known that antiestrogens are able to induce nuclear translocation of estrogen receptor [2,3] and some, but not all, estrogen-specific responses [4]. It is therefore likely that the reason for their weak estrogenic activity is due to an alteration of the ER interaction with chromatin acceptor sites [5]. Since these acceptor sites are likely to consist, at least partly, of non-specific double-stranded DNA [6,7], the interaction between DNA and ER in vitro has also been studied. It has been shown that the ER activated by antiestrogen is able to interact in vitro with DNA [8,9] but the degree of this interaction has not been quantified and compared to that obtained with estrogens.Two major hypotheses are presently available to explain the antagonist activity of these drugs. The first and simplest one is that the binding of antiestrogens is less efficient than estrogen at activating the ER and triggering biological responses. In support of this idea, we have recently found that the rate of dissociation of estrogen and antiestrogen from the ER are differently affected by molybdate, suggesting that ER is differently activated by these two types of ligands [lo]. The second hypothesis is that the antiestrogen behaves as a full estrogen agonist on the ER but blocks estrogen responses through another mechanism resulting from its interaction with other cellular components such as antiestrogen-binding proteins [Ill. To help in discriminating between these two possibilities and in an attempt to find a molecular explanation for the weak or partial estrogenic activity of antiestrogen, we have studied the degree of interaction of the ER with calf thymus DNA.The putative se...

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Effect of Antiestrogens on Uterine Estradiol Receptors

Cited by 27 publications

References 26 publications

Interaction of the anti-oestrogen, nafoxidine hydrochloride, with the soluble nuclear oestradiol-binding protein in chick liver

Interaction of the anti-oestrogen, nafoxidine hydrochloride, with the soluble nuclear oestradiol-binding protein in chick liver

Effect of Cis- and Trans-Clomiphene on the Uterine Blood Flow of Oophorectomized Ewes

Estrogen-Receptor-DNA Interaction

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