Evidence that the antiestrogen binding site is a histamine or histamine-like receptor

Brandes, Lorne J.; MacDonald, Linda; Bogdanovic, R.Patricia

doi:10.1016/0006-291x(85)90271-2

Cited by 67 publications

(22 citation statements)

References 5 publications

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“…Tamoxifen also inhibits the growth of MCF 7 mammary carcinoma cells and not all of these effects are reversed by estradiol [30]. Tamoxifen also binds to histamine-like [31] receptors which may be of the H3 type acting as autoinhibitory for histamine secretion [79]. Even though it is hard to make comparisons between species, it may be reasonable to suggest that use of tamoxi fen may have implications for the therapy of a variety of neuroimmunoendocrine syndromes [7,56,57,80].…”

Section: Discussionmentioning

confidence: 99%

“…In higher concentrations, tamoxifen is cytotoxic to these cells [30,83]. There are also reports that tamoxifen binds to histamine-like [31] and dopamine receptors [32], as well as to cytochrome P-450 [33], while it appears to inhibit the action of calmodulin [34][35][36] and protein kinase C (PKC) [37][38][39], Here, we investigated for the first time the possible ef fect of estradiol on mast cell secretion induced by immu nologic and nonimmunologic means in an attempt to ex plain mast cell involvement in neuroimmunoendocrine disorders. The effect of testosterone and tamoxifen on mast cell secretion was also investigated using nonimmu nologic secretagogues.…”

Section: Introductionmentioning

confidence: 99%

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Estradiol Augments while Tamoxifen Inhibits Rat Mast Cell Secretion

Vliagoftis

Dimitriadou

Boucher

et al. 1992

Int Arch Allergy Immunol

150

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Mast cells have been studied extensively for their involvement in allergic reactions, where they secrete numerous powerful mediators in response to immunoglobulin E and specific antigens. However, they are also triggered by neuropeptides, they have been found in close contact with neurons, and they are activated in diseases such as angioedema, interstitial cystitis and irritable bowel disease, the prevalence of which is much higher in women. When tested on purified rat peritoneal mast cells, 17β-estradiol augmented secretion of histamine and serotonin, starting at 1 μM and in a dose-dependent manner, whether stimulated by the mast cell secretagogue compound 48/80 or the neuropeptide substance P. However, 17β-estradiol did not augment mast cell secretion stimulated by immunoglobulin E and specific antiserum indicating that immunologic stimulation is under different regulation. Testosterone inhibited secretion induced by compound 48/80. Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibited serotonin and histamine release from purified rat peritoneal mast cells triggered by compound 48/80 or substance P. Tamoxifen also inhibited the increase in intracellular free Ca²⁺ originating from an influx of extracellular Ca²⁺ in response to compound 48/80. Moreover, tamoxifen antagonized the synergistic effect of phorbol myristate and the cation ionophore A23187 on mast cell secretion, suggesting that tamoxifen’s inhibition may be due to regulation of protein kinase C activity. Tamoxifen may, therefore, have a beneficial effect in other neuroimmunoendocrine disorders both through estrogen receptor blockade and inhibition of mast cell secretion.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Estradiol Augments while Tamoxifen Inhibits Rat Mast Cell Secretion

Vliagoftis

Dimitriadou

Boucher

et al. 1992

Int Arch Allergy Immunol

150

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“…These include: muscarinic receptors (Ben-Baruch et al, 1982), dopamine receptors (Hiemke & Ghraf, 1984), histamine receptors (Brandes et al, 1985), cytochromes P-450 (Ruenitz et al, 1984), calmodulin (Lam, 1984), protein kinase C (O'Brian et al, 1985) and a high affinity binding site of unknown function termed the antioestrogen binding site (AEBS) (Sutherland & Foo, 1979;Sutherland et al, 1980). The roles, if any, of these binding sites in mediating any of the effects of nonsteroidal antioestrogens, in particular their apparently non-oestrogen-receptor-mediated effects, have not been directly established, although workers in this laboratory have shown that analogues with high affinity for AEBS have more potent antiproliferative effects on breast cancer cells in vitro than analogues with low affinity for AEBS , 1985.…”

Section: Introductionmentioning

confidence: 99%

Microsomal binding sites for antioestrogens in rat liver. Properties and detergent solubilization

Watts¹,

Sutherland²

1986

Biochemical Journal

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The properties ofan antioestrogen binding site (AEBS), which has high affinity and specificity for nonsteroidal antioestrogens and structurally related compounds, have been studied in rat liver microsomes. When subcellular organelles were separated on Percoll density gradients the distribution of the AEBS paralleled that of NADPH-cytochrome c reductase, indicating that the AEBS is associated with the endoplasmic reticulum. Saturation analysis showed that [3H]tamoxifen was bound to a single class of saturable binding sites in liver microsomes with a KD of 0.9 + 0.1 nm at 0 'C. The equilibrium KD was not significantly different at 22 'C. The KD calculated from the association and dissociation rate constants for [3H]tamoxifen binding at 0 'C and 22 'C was compatible with the KD measured at equilibrium. Ligand specificity studies using tamoxifen analogues showed qualitatively similar structure-affinity relationships for the AEBS from both rat liver and the MCF 7 breast cancer cell line. In general structural modifications caused correspondingly greater changes in affinity for rat liver AEBS than for MCF 7 AEBS. The AEBS was solubilized from microsomal membranes with sodium cholate. This was the only detergent of nine tested that solubilized the site in high yield without loss of activity. Solubilization using cholate was more effective in the presence of 1 M-NaCl. In the solubilized state there was an apparent loss of [3H]tamoxifen binding activity which could be restored by dilution ofthe detergent. Gel filtration indicated an Mr of440 000-490 000 for the AEBS-cholate complex. These studies demonstrate that rat liver contains high concentrations of a microsomal AEBS which has similar properties and specificity to the AEBS previously described in human breast cancer cells. This site can be solubilized by sodium cholate to supply material suitable for further purification. INTRODUCTIONThe nonsteroidal antioestrogens, structurally related synthetic compounds, are competitive inhibitors of the binding of oestradiol to the intracellular oestrogen receptor. Numerous studies of the molecular interactions

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“…Such sites in clude: muscarinic receptors [16], dopamine receptors [17], histamine receptors [18], cy tochrome P-450 [19], calcium channels [20], calmodulin [21], protein kinase C [22] and a specific high affinity binding site [23][24][25] called antiestrogen-binding site (ABS). Each of these sites may be a potential mediator of the effects of high dose antiestrogens.…”

Section: Alternative Mechanisms Of Action Of Antiestrogensmentioning

confidence: 99%

“…data]. The effect of antihistamine (H| and H2 antago nists) has been studied in detail by Brandes et al [18] and the probability that the H, or H2 receptor [30] could be the mediator of the effects of high dose antiestrogens has also been excluded.…”

Section: Alternative Mechanisms Of Action Of Antiestrogensmentioning

confidence: 99%

Antiestrogens, Different Sites of Action than the Estrogen Receptor?

Faye¹,

Fargin²,

Valette³

et al. 1987

Horm Res

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Nonsteroidal antiestrogens display antagonistic as well as agonistic properties when compared with estrogens. These observations and studies of their molecular interactions suggest that part of their activity is mediated through estrogen receptor (ER)-mediated pathways. However, other data, concerning mainly effects on growth and cellular proliferation, cannot be explained on this basis. Recent investigations have shown binding of these molecules to a number of other intracellular binding sites beside ER. Using different cell variants of the human breast cancer cell line MCF-7 we could confirm the peculiar role of one of these sites, the specific antiestrogen-binding site (ABS). Published data on ABS are critically reviewed.

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Evidence that the antiestrogen binding site is a histamine or histamine-like receptor

Cited by 67 publications

References 5 publications

Estradiol Augments while Tamoxifen Inhibits Rat Mast Cell Secretion

Estradiol Augments while Tamoxifen Inhibits Rat Mast Cell Secretion

Microsomal binding sites for antioestrogens in rat liver. Properties and detergent solubilization

Antiestrogens, Different Sites of Action than the Estrogen Receptor?

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