Antiestrogen-Binding Sites Distinct from the Estrogen Receptor: Subcellular Localization, Ligand Specificity, and Distribution in Tissues of the Rat*

Sudo, Katsuichi; Monsma, Frederick J.; Katzenellenbogen, Benita S.

doi:10.1210/endo-112-2-425

Cited by 185 publications

(71 citation statements)

References 29 publications

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“…The control treated only with tamoxifen showed no response of the hepatocytes in terms of VTG production. This allows us to consider the action of tamoxifen as purely antagonistic in the system we use despite the fact that other studies demonstrated that tamoxifen action is quite complex since this drug can interact on more than one binding site and can be both agonist and antagonist of E 2 on cell growth [58,59]. It should be noted that the inhibition, of the 'estrogenic activity' of both androgens and progestagens by tamoxifen appears to be a real inhibition, rather than a toxic effect of tamoxifen.…”

Section: Resultsmentioning

confidence: 99%

Vitellogenin synthesis in cultured hepatocytes; an in vitro test for the estrogenic potency of chemicals

Pelissero

Flouriot

Foucher

et al. 1993

The Journal of Steroid Biochemistry and Molecular Biology

266

108

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Smnmary--We describe here an/n vitro technique to assess the estrogenic activity of chemicals. This technique is based on rainbow trout hepatocytes incubated in a basic medium free of any additional growth factors or estrogenic chemicals and uses the production of vitellogenin (VTG) as a marker for the estrogenic potency of the compounds tested. The system allows at least some of the metabolic transformations which are undertaken by the liver cells/n vivo and could therefore be used for xenobiotic compounds which exhibit estrogenic activities after liver metabolic transformation. A dose-response curve was always consistently obtained using estradiol-17fl (E2), with a mid point at around 100 nME 2 and a maximum response at around 1000nM. Established estrogens such as 17al ethynylestradiol (EE2) or diethylstilboestrol (DES) were also tested. EE 2 appeared to be equipotent with E2 and DES slightly less potent. E2 conjugates were, perhaps surprisingly, also very potent. Estradiol-3-sulfate was equipotent with E2 and estradiol-17fl-glucuronide approx. 10% as potent. Other steroids such as androgens and progesterone, though active in the bioassay, were 3 orders of magnitude less potent than E 2. Of the various steroids tested, only cortisol, at concentrations up to 50 #M, was completely inactive. Six different phytoestrogens were tested in the assay. All were weakly estrogenic, possessing approximately one thousanth the potency of E 2 (they were as potent as the androgens and progesterone). All six phytoestrogens, as well as the androgens and progesterone, were tested in the presence of tamoxifen. In all cases tamoxifen reduced the production of VTG significantly, demonstrating that the estrogenic action of all of these compounds was most likely mediated by the E 2 receptor. The potencies determined here may not reflect the situation/n vivo but can provide complementary results about the activity of chemicals which need an hepatic metabolization to be estrogenic. Hepatocyte cultures would profitably be developed in other species to sustain these results.

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Section: Resultsmentioning

confidence: 99%

Vitellogenin synthesis in cultured hepatocytes; an in vitro test for the estrogenic potency of chemicals

Pelissero

Flouriot

Foucher

et al. 1993

The Journal of Steroid Biochemistry and Molecular Biology

266

108

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“…The mechanism of such ER-independent inhibition of tumor cell growth by Tam is not clearly known. Binding to so-called anti-estrogen sites and the inhibitions of calmodulin and protein kinase C (PKC) are considered to be some known additional sites of action of Tam-related agents (12)(13)(14)(15)(16).…”

Section: Tamoxifen (Tam)mentioning

confidence: 99%

Tamoxifen Modulates Protein Kinase C via Oxidative Stress in Estrogen Receptor-negative Breast Cancer Cells

Gundimeda

Chen

Gopalakrishna

1996

Journal of Biological Chemistry

152

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“…In our studies aimed at understanding estrogen and antiestrogen action in estrogen-responsive cells, we have been struck by the curious observation that antiestrogens suppress growth below that of control cells in the apparent absence of estrogens (6,11), suggesting that this growth suppression might be mediated by an estrogen-noncompetitive process ( [11][12][13][14] or that cells in the control media might be inadvertently exposed to an estrogenic stimulus.…”

mentioning

confidence: 99%

Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture.

Berthois¹,

Katzenellenbogen²,

Katzenellenbogen³

1986

Proc. Natl. Acad. Sci. U.S.A.

1,076

543

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Although much attention has been paid to the removal of hormones from sera and to the development of serum-free media for studies on hormone-responsive cells in culture, little consideration has been given to the possibility that the media components themselves may have hormonal activity. We have found that phenol red, which bears a structural resemblance to some nonsteroidal estrogens and which is used ubiquitously as a pH indicator in tissue culture media, has significant estrogenic activity at the concentrations (1545 IAM) at which it is found in tissue culture media. Phenol red binds to the estrogen receptor of MCF-7 human breast cancer cells with an affinity 0.001% that of estradiol (Kd = 2 x 10-S M). It stimulates the proliferation of estrogen receptor-positive MCF-7 breast cancer cells in a dose-dependent manner but has no effect on the growth of estrogen receptor-negative MDA-MB-231 breast cancer cells. At the concentrations present in tissue culture media, phenol red causes partial estrogenic stimulation, increasing cell number to 200% and progesterone receptor content to 300% of that found for cells grown in phenol red-free media, thereby reducing the degree to which exogenous estrogen is able to stimulate responses. The antiestrogens tamoxifen and hydroxytamoxifen inhibit cell proliferation below the control level only when cells are grown in the presence of phenol red; in the absence of phenol red, the antiestrogens do not suppress growth. The estrogenic activity of phenol red should be considered in any studies that utilize estrogen-responsive cells in culture.

show abstract

Antiestrogen-Binding Sites Distinct from the Estrogen Receptor: Subcellular Localization, Ligand Specificity, and Distribution in Tissues of the Rat*

Cited by 185 publications

References 29 publications

Vitellogenin synthesis in cultured hepatocytes; an in vitro test for the estrogenic potency of chemicals

Vitellogenin synthesis in cultured hepatocytes; an in vitro test for the estrogenic potency of chemicals

Tamoxifen Modulates Protein Kinase C via Oxidative Stress in Estrogen Receptor-negative Breast Cancer Cells

Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture.

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