Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00627 (MAP)
 15,705 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of action of the copper IUD was investigated in the rabbit uteri. The effects of copper on steroid-hormone-receptor interaction and the morphologic effects of copper were studied, and the uterine copper content was measured. In vivo and in vitro results were compared. Uterine cytosol was produced by daily sc injections of 50 mcg 17beta-estradiol for 8 days into immature female rabbits. 2 days later the rabbits were decapitated and the cytosol prepared from homogenized uteri. Radioactive steroids were purchased. Radioactivity was counted with a Packard 3390 liquid scintillation spectrometer. Progesterone binding to uterine cytosol was measured. Techniques used are described. On Day 8 of priming of female immature rabbits, a copper IUD was inserted into the right uterine horn. Progesterone (1 mg) or 17beta-estradiol (50 mcg) was injected sc for another 7 days. The rabbits were decapitated on Day 8 and their uteri excised. Sections were prepared and studied histologically. Each horn was minced and homogenized. The supernatant was used as cytoplasm and the copper content of each uterine horn measured. The binding capacity of the estrogen receptor was less affected by copper than was that of the progesterone receptor. Copper was a competitive inhibitor of steroid-ho rmone-receptor binding. Results indicate that copper acts through direct interference at the steroid-binding site of the receptor resulting in the increased contraceptive effect of the copper IUD. A 5-20% sucrose linear gradient centrifugation showed that estrogen and progeste rone receptors, which both sedimented at 8S, were changed to more sedimentary forms in the presence of 10-4 M Cu ++ and were dissociated to a 6.5S form with (some loss of steroid hormone binding affinity at 10-2 Cu ++. This dissociation and aggregation of the receptor macromolecules may cause biologic inactivation of the receptors. Histological study of the uteri of rabbits bearing the copper 7 IUD showed that progestational proliferation and estrogenic activity were inhibited. The copper content of the cytoplasm was increased in the presence of a copper IUD. The greater stability of the estrogen receptor in the presence of copper suggests an increased estradiol uptake in rat uteri bearing a copper IUD. The concentration of 1.4 X 10 -6 M Cu ++ appears to be effective in the steroid-hormone-receptor interaction. However, this effect by copper cannot exclude the coexistence of some other mechanism in these phenomena.
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PMID:The mechanism of action of the copper intrauterine device. 18 Dec 76

Norethindrone (ENT), which is a representative in estrane series of progestogen, is not only strongly progestational but also estrogenic and in some cases, antiestrogenic. To understand progestational effect and antiestrogenic effect, the interactions of ENT on estrogen and progestogen receptors were studied in the uterine cytosol of white female rabbit. The 274,200 X G supernatant of uterine homogenate was used as cytosol. 3H-Estradiol, 3H-Progesterone, 3H-ENT or cold ENT were incubated with uterine cytosol at 4 degrees C for 2 hours. Results are as follows: 1. Sucrose gradient centrifugation [5 approximately 20% linear and 40,000 rpm (159,200 X G) for 16 hours at 4 degrees C]: ENT was bound to extrogen 8S receptor in immature rabbit uterus (Fig. 2 & 3), and to progestogen 8S receptor in estrogen primed rabbit uterus (Fig. 5). 2. Kinetic study, determined by dextran coated charcoal (0.001% dextran and 0.1% charcoal): (1) In the uterine cytosol of immature rabbit, 3H-estradiol-receptor binding was observed with Kd divide by 3.6 X 10-9 M and it was revealed that ENT was a competitive inhibitor to this binding with Ki divide by 2.6 X 10-6 M, as in Fig. 6. (2) 8S component, obtained by centrifugation of uterine cytosol (Fig. 1) in estrogen primed rabbit, binds 3H-progesterone with Kd divide by 8.1 X 10-10 M and Bm (maximal binding sites) divide by 5.0 X 10-8 M/mg of protein, and ENT was a competitive inhibitor in this binding with Ki divide by 2.3 X 10-9 M (FIG. 7 & 8). 3H-ENT-8S binding was demonstrated with Kd divide by 1.1 X 10-9 M and Bm divide by 8.7 X 10-8 M/mg of cytosol protein (Fig. 8). These results indicate: (a) ENT is bound to both estrogen and progestogen receptors in 8S macromolecules of uterine cytosol, (b) competitive inhibition of ENT to these bindings indicated that ENT is bound to these receptors at the steroid binding sites where estradiol and progesterone bind to, (c) ENT has much more affinity to progestogen receptor (Ki divide by 2.3 X 10-9 M) than to estrogen receptor (Ki divide 2.6 X 10-6 M), (d) while ENT is bound to progestogen and estrogen receptors at the same time, Bm of ENT (8.7 X 10-8 M/mg of cytosol protein) is more than Bm of progesterone (5.0 X 10-9 M/mg of cytosol protein), and Kd of ENT (1.1 X 10-9 M) was less than Ki of ENT (2.3 X 10-9 M) in the binding to progesterone-receptor. Biologically, while ENT is bound to progestogen -receptor with high affinity and to estrogen receptor with low affinity, ENT is actually progestational in low dose and antiestrogenic in high dose but the anti-estrogenicity seems to be incomplete in vivo as ENT may be metabolized to a potent estrogenic compound, ethinyl estradiol
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PMID:[Interaction of norethindrone on estrogen and progesterone receptors in the rabbit uterine cytosol (author's transl)]. 18 90

Aldehyde-resistant, diaminobenzidine-stained endogenous peroxidases form ideal markers for the biochemical endpoints of hormone stimulation and differentiation of certain mammalian cells and tissues. The lactoperoxidase (LPO)-type of endogenous peroxidases are synthesized by the acinar cells of the salivary, Harderian, lacrimal and mammary glands and are present in their secretions. These LPO-type enzymes, that are inhibited by cyanide and aminotriazole, appear to operate extracellularly as bactericidal agents in milk and in other biological fluids. In the mammary gland, lactoperoxidase is a consistent marker enzyme for differentiated acinar cells engaged in lactogenesis. Myeloperoxidase (MPO)-type endogenous peroxidases are prominent markers for the GERL endomembrane system and differentiated lysosomes in certain cells of the reticuloendothelial system and phagocytes. MPO is prominent within eosinophils, peritoneal macrophages and in Kupffer cells. The MPO-type endogenous peroxidases function primarily within lysosomes as bactericidal agents. Thyroid peroxidase (TPO) is relegated to the cisternae of the granular endoplasmic reticulum and Golgi apparatus, to apical cytoplasmic vesicles and to the luminar cell membrane surface of acinar cells. The enzyme is probably activated at release and functions both in the organification reaction (T leads to To) and in the biosynthesis of thyroxine. Thyroid stimulating hormone (TSH) appears to play a key role in the regulation of TPO levels and activity in the thyroid gland. Certain tissues displaying growth-dependency on estrogen (i.e., uterus, cervix, vagina and the DMBA-induced rat mammary tumor) synthesize and secrete endogenous peroxidase into their lumina. These enzymes serve as important marker proteins of estrogen action, in that they occur distal to the binding of estrogen to its receptor protein. Estrogen antagonists, particularly CI-628 (Parke-Davis) and Nafoxidine (Upjohn) that appear to function through the estrogen receptor mechanism, also induce synthesis of the reproductive tract endogenous peroxidase but inhibit growth of these tissues. Progesterone antagonizes the synthesis of the reproductive tract peroxidases and inhibits growth of the tissues as well, in part, through the reduction of the cytosol estrogen receptor protein. Endogenous peroxidase activity appears to represent a reliable marker for rodent breast cancer tissues displaying dependency for estrogen and is of potential interest as a diagnostic marker protein in human breast cancer. Rat uterine peroxidase (UP) has been investigated by microelectrophoretic techniques. The molecular weight of UP has been determined in the range of 100,000 by using polyacrylamide gradient gels in the absence and presence of nonionic and anionic detergents. The isoelectric point of UP is located between pH 4.5 and 5.9. Employing the two-dimensional combination of isoelectric focusing and gel gradient electrophoresis, UP was separated into two subunits, one having a molecular weight of 70,000, the other less than 20,000.
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PMID:Mammalian endogenous peroxidases as cellular markers and as biosynthetic endpoints of hormone-mediated activity: viewpoint from cytochemistry. 22 20

Endocrine hormone treatment has been found to be effective in treating metastatic breast cancer in 20-40% of the cases. The effectiveness of this treatment can be predicted to a certain extent by determining whether the hormone receptors in the tumor tissue react positively or negatively when incubated with highly active hormones, e.g. H3-17 beta-estradiol. Estrogen receptors are found in 60-70% of primary tumors and 40-50% of tissue samples from metastatized tumors. Estrogen receptors are more frequently found in post-menopausal women than in women who are still menstruating. Progesterone receptors have been found in 20-40% of all investigations undertaken, androgen receptors in 20-30%, and corticosteroid receptors in 20-50%. A remission rate of 56% has been achieved after endocrine therapy of those with positive estrogen receptor tests, compared to 10% among those with negative tests. The correlation between the receptor test results and (the success of) endocrine therapy is not very high; this could be a factor determined by the cellular constitution of a tumor. The remission rate is 75% among patients with positive receptor tests for both estrogen and progesterone. Faulty lab techniques could be responsible for low correlation. Determination of the receptor activity of both the primary tumor and its metasases, or immunological or immunohistological determination of receptor activity may improve the usefulness of the test in determining tumor reaction to endocrine hormone treatment.
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PMID:[The clinical value of hormone receptors in the treatment of breast neoplasms]. 54 83

Properties and isolation possibilities of an estradiol (E2) binding protein from male rat liver cytosol as possible estrogen receptor are studied. The protein is found to differ considerably in a number of characteristics from well-known receptor and non-receptor rat proteins, specifically binding estrogen. Equilibrium constant of E2-protein interaction is 1-10(8) M-1, the concentration of protein binding sites is 1.3 million per cell. Processes of E2 association with protein and the complex dissociation proceed with a very high rate. E2 and, at lesser degree, estrone, testosterone and 5-alpha-dihydrotestosterone compete for binding sites of protein with 3H-E2. Progesterone, corticosterone and a synthetic estrogen, hexestrol, denot compete. The protein studied is thermolabile and sensitive to the effect of pronase and sulfhydryl reagents. Characteristics of the protein are as follows: sedimentation coefficient--3.6S; Stockes' radius--23--25 A; friction coefficients ratio--1.05--1.12; molecular weight--36000--39000. The protein is not revealed in the liver of female rats. Ammonium sulphate precipitation, gel filtration and ionic exchange chromatography made possible to obtain 50-fold purified protein preparation.
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PMID:[Detection and preliminary characterization of a particular estrogen-binding protein in the liver of male rats]. 55 7

Uterine peroxidase enzyme activity has been studied as a marker for estrogen action in the uterus to help clarify the mechanism of estrogen action and its modulation by antiestrogens and progestins. Estrogen-induced increases in peroxidase were found to closely parallel increases in uterine weight and DNA content in the castrate rat. In the cycling female rat, uterine peroxidase levels were highest during proestrus and estrus and the lower levels of metestrous and diestrous uteri could be raised to estrous levels by administration of estrogen. However, the estrous levels were not further increased by estrogen treatment. The antiestrogen, CI628, while a very weak inducer of uterine peroxidase, is an effective antagonist of the estrogen induction of the enzyme. The prolonged duration of this CI628-effected inhibition corresponds to the prolonged depletion of cytoplasmic estrogen receptor seen with CI628 treatment. Progesterone, R5020 and norethindrone were also found to be effective antagonists of estrogen-induced uterine peroxidase. Medrogestone and clogestrone, less potent progestins in the rat, were also less effective antagonists of peroxidase induction. Since progesterone was found to inhibit peroxidase induction due to both estrone and diethylstilbestrol, as well as estradiol, it is considered unlikely that this antagonism relates to progestin-induced increases in uterine 17 beta-hydroxysteroid dehydrogenase. Rather, it is proposed that progestins, acting through progestin receptor, may have a more direct role, possibly acting at the level of the genome to repress the expression of estrogen-induced products.
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PMID:Steroid hormone regulations of uterine peroxidase activity. 57 50

Estrogen receptors (ER) were measured on specimens taken from 27 patients with benign breast conditions and 109 patients with breast cancer. Using sucrose gradient assay, 15% (4/27) of benign lesions and 56% (61/109) of malignant tumors were estrogen receptor-positive (ER-positive means 8S or 8S+4S levels more than 7 fmoles/mg cytosol protein). Progesterone receptors (PR) were tested on specimens from 28 patients and 39% (10/26) of the cancers were PR-positive. ER protein activity was not correlated with stage, histology, size of primary lesions, or extent of axillary or distant metastasis. Tumors with low ER levels are more likely to recur, and recurrent tumors after longer disease-free intervals are more likely to be ER-positive. Detailed analysis showed that ER levels did correlate with age and serum albumin levels. Concentrations of serum alpha1-globulin were decreased, while IgG and IgM were significantly increased among patients with positive ERs. Eighteen evaluable patients with advanced breast cancer had endocrine therapy, 13 had objective response. Twelve of these 13 had 8S receptor above 10 fmoles/mg, or 4S above 15 moles/mg, or 8S+4S above 25 fmoles/mg. The one exceptional patient had tumor with high PR but without detectable ER.
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PMID:Steroid receptors study in breast carcinoma. 74 84

A complementary DNA synthesized from ovalbumin mRNA was used in hybridization experiments to study the early effect of estrogen and progesterone on the accumulation of ovalbumin mRNA sequences in the chick oviduct. Chicks treated with estrogen withdrawn from the hormone maintain a steady level of 60 molecules of ovalbumin mRNA per tubular gland cell, at least 80% of which are localized in the cytoplasm. After estrogen administration, there is a 3- to 4-hour lag before a rapid increase in the number of ovalbumin mRNA sequences and a parallel increase in ovalbumin synthesis. Progesterone causes a more rapid increase in both ovalbumin mRNA sequences and ovalbumin synthesis with a lag period of only 90 min. The hybridization results demonstrate that both estrogen and pregesterone affect the amount of ovalbumin mRNA per cell. The 3-hour lag period seen with estrogen appears to be caused by some event after the binding of the estrogen receptor to chromatin but prior to change in the rate of transcription of the ovalbumin gene.
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PMID:Induction of ovalbumin mRNA sequences by estrogen and progesterone in chick oviduct as measured by hybridization to complementary DNA. 117 63

In this study we analyzed the covalent binding to proteins of 17 beta-estradiol (E2), retinoic acid (RA), and progesterone in MCF-7 and MCF-7/AdrR cells. MCF-7 cells have receptors for E2 and progesterone. MCF-7/AdrR cells do not have these receptors. After a 1-day incubation period with either [3H]E2, [3H]progesterone, or [3H]RA the levels of covalently bound radioactivity was between 1.4- to 2-fold greater in MCF-7 cells than in MCF-7/AdrR cells. We analyzed the labeled proteins with two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and fluorography. About 40 proteins were labeled by E2 in MCF-7 cells and about 10 of these proteins were the only proteins labeled by E2 in MCF-7/AdrR cells. We saw that the same 8 proteins were labeled by RA in both cell lines. Progesterone labeled 2 proteins with M(r) values of 37,000 and 20,000 in MCF-7 cells. These 2 proteins had mobilities that were the same as proteins that were labeled by either E2 or RA in both MCF-7 and MCF-7/AdrR cells. Besides these 2 proteins, we saw proteins of M(r) 51,000 (p51) and 55,000 that were covalently labeled by E2 in MCF-7 cells and by RA in both MCF-7 and MCF-7/AdrR cells. The p51 had the same mobility on 2D-PAGE as an 8-azido-[32P]cAMP-labeled protein. This protein is probably RII alpha, the type II cAMP-binding regulatory subunit of type II cAMP-dependent protein kinase. These results suggest that the estrogen receptor, while not obligatory, might still modulate the covalent linkage of E2 to protein. In addition, our results raise the possibility that some effects of some ligands of the thyroid/steroid hormone receptor family may involve the covalent linking of these hormones to proteins, including RII alpha.
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PMID:The covalent labeling of proteins by 17 beta-estradiol, retinoic acid, and progesterone in the human breast cancer cell lines MCF-7 and MCF-7/AdrR. 132 24

Estradiol produces a large increase in the uterine level of c-fos mRNA, which is maximum in 3 h. The administration of progesterone antagonizes this estrogen-induced increase in protooncogene transcript levels in both the rat and mouse. The inhibitory effect of progesterone is observed within 1 h after hormone treatment and persists for 9-18 h. In the rat, this effect can be observed at a dose of 0.25 mg progesterone and is maximum at a dose of 2.5 mg. A similar inhibition of fos mRNA levels after estrogen administration is produced by the glucocorticoid dexamethasone, but not by androgens or mineralocorticoids. Progesterone does not block the induction of c-jun or c-myc mRNA by estradiol. Uterine levels of c-fos mRNA observed after treatment with the phorbol ester phorbol 12-myristate 13-acetate are not decreased by a 3-h pretreatment with progesterone. Under the conditions of our experiments, progesterone does not decrease occupied levels of nuclear estrogen receptors in the uterus after estradiol administration. These findings are consistent with a mechanism in which progesterone inhibits transcriptional activation by the estrogen receptor at the level of the c-fos gene.
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PMID:Progesterone inhibits the estrogen-induced expression of c-fos messenger ribonucleic acid in the uterus. 137 96


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