Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of estrogens on hepatic beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity and cholesterol in serum and liver of ovariectomized rats on normal diet 2% cholestyramine diet or 2% cholesterol diet was investigated. Estrogen administration to ovariectomized rats on normal diet resulted in increased reductase activity and was correlated with decreased serum cholesterol and increased liver cholesterol levels with mestranol (ME), ethinyl estradiol (EE) and estradiol benzoate (EB, 250 microgram) but increased serum and liver cholesterol levels with 25 microgram and 100 microgram EB administration. The increased stimulation of reductase activity by estrogen administration was abolished when rats were fed a 2% cholesterol diet. Cholestryramine feeding markedly increased reductase activity in livers of ovariectomized rats. These studies show that estrogens are not absolutely required for the stimulation of reductase activity and therefore is consistent with the model in which cholesterol functions as a feedback repressor of reductase activity.
Steroids 1981 Jun
PMID:Effect of estrogens on beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity and cholesterol levels. 729 35

This study reports the formation and isolation of a diethylstibestrol-dimethylsulfoxide (DES-DMSO) adjunct and Z-3, 4-di (p-hydroxyphenyl)-2-hexene (psi-DES) from trans-DES. The presence of psi-DES was indicated by NMR and mass spectrometry and confirmed by direct comparison to a reference sample. High resolution NMR (360 MHz) along with the comparison of the chemical shift values of methine and methyl protons attached to carbon-carbon double bonds in Z and E isomers of 3-substituted-2-pentenes and dienestrol derivatives were used in postulating the Z-stereochemistry for psi-DES. A NMR additive increment method was useful for the comparison of the chemical shift values of methine protons in psi-DES and other literature compounds. Nuclear Overhauser Enhancement (NOE) confirmed the Z-stereochemistry of psi-DES.
Steroids 1981 Nov
PMID:Isomerization of trans-diethylstilbestrol to pseudo-diethylstilbestrol. 732 87

The preventive effects of estrogens on FeSO4-induced lipid peroxidation are closely correlated with their inhibition of Fe(II) oxidation during peroxidation. Estrogens affected the redox status of iron in aqueous solution with varying degrees of effectiveness. 2-Hydroxyestradiol substantially decreased the oxidation of Fe(II) and was the most potent Fe(III) reductant. Diethylstilbestrol and 4-hydroxyestradiol also exhibited reduction properties, whereas the phenolic estrogens 17 beta-estradiol, estrone, and 17 alpha-ethynylestradiol displayed slighter or no effects. Present results demonstrate that catecholestrogens and diethylstilbestrol directly alter the iron redox chemistry, this fact probably being involved in the antioxidant effects of these molecules.
Steroids 1995 Nov
PMID:Effects of estrogens on the redox chemistry of iron: a possible mechanism of the antioxidant action of estrogens. 858 3

The hypothesis that estrogen-induced pituitary tumors are mediated by the neuropeptide galanin was tested using tumor-resistant (Sprague-Dawley; SD) and tumor-sensitive (Fischer 344; F344) rat strains. Diethylstilbestrol (DES) increased expression of galamin mRNA in both strains after 1, 2, and 4 weeks of treatment and doubled pituitary weights in F344 rats while pituitary weights in SD rats were unchanged by DES treatment. In F344 rats, both the expression of galanin mRNA and pituitary weights increased linearly with the length of DES treatment. In SD rats however, despite increasing levels of galanin mRNA, pituitary weights did not increase. These data indicate that galanin gene expression, by itself, is not sufficient to account for increased pituitary growth. However, our data do not rule out the possibility that galanin has an indirect role in promoting pituitary growth.
Steroids 1996 Aug
PMID:Effect of estrogen on the expression of galanin mRNA in pituitary tumor-sensitive and tumor-resistant rat strains. 887 Jan 66

Estrogen sulfamates are promising hormones by oral administration. Therefore, generally applicable and convenient methods for the multigram synthesis of these derivatives are desirable. Numerous estra-1,3,5(10)-trienes derived from estrone, estradiol. 14 alpha,15 alpha-methylenestradiol, ethinylestradiol, and estriol have been esterified with sulfamoyl chloride and N-methylsulfamoyl chloride by a novel approach involving the use of 2,6-di-tert-butylpyridines as bases and chemoselective hydroxy group protections. These pathways circumvent the nonselective formation of esters and side reactions by in situ generated azasulfenes. For toxicological and clinical studies a new synthesis of estrone sulfamate on a 100-g scale was developed using dimethylformamide as the solvent and base.
Steroids 1996 Dec
PMID:Synthesis of estrogen sulfamates: compounds with a novel endocrinological profile. 898 40

Estrogen treatment affects the hepatic synthesis and/or secretion of several proteins involved in clinically important pathological processes such as atherosclerosis, hypertension, and thrombosis. The endocrine regulation of the estrogen receptor (ER) concentration in primary cultures of rat hepatocytes was studied. Human growth hormone (hGH) and dexamethasone (DEX) in combination increased ER concentration 6-fold and ER mRNA levels 2.5-fold. These effects were not significantly different from those observed after treatment with the purely somatogenic bovine growth hormone (GH) in combination with DEX. Treatment with the lactogen ovine prolactin in the presence or absence of DEX did not significantly affect ER or ER mRNA concentrations. Triiodothyronine treatment at the most effective concentration (50 nM) increased ER and ER mRNA levels twofold. Medium supplementation with estradiol (0.1 nM) throughout the experiment did not affect the response to treatment with hGH and DEX. Treatment with high concentrations of ethinylestradiol in combination with hGH and DEX, however, increased the ER level twice as much as hGH and DEX without addition of estradiol or ethinylestradiol, whereas the ER mRNA concentration was the same in both the GH+DEX group and GH+ DEX+ (estradiol or ethinylestradiol) groups. These data indicate the importance of GH in combination with glucocorticoids for the maintenance of ER concentrations in the rat liver. Thyroid hormones may be of some, although minor importance, whereas the data suggest that prolactin is not directly involved in hepatic ER regulation.
Steroids 1997 Oct
PMID:Hormonal regulation of the estrogen receptor in primary cultures of hepatocytes from female rats. 938 11

Diethylstilbestrol (DES) is a well-characterized carcinogen in humans and animals although its mechanisms of carcinogenicity are not yet known. While the estrogenic activity of DES is important, there is evidence that oxidative metabolism also plays an important role for its toxicity. DES is oxidatively metabolized in vivo and in vitro to a number of compounds including diethylstilbestrol-4',4"-quinone (DQ), an unstable and reactive intermediate, and Z,Z-dienestrol (ZZ-DIEN). Estrogen receptor (ER) binding assays with mouse uterine cytosol indicate that DES, DQ and ZZ-DIEN have relative binding affinities of 286, 3.6 and 0.3, respectively, relative to estradiol as 100. In addition, DQ binds irreversibly and specifically to ER suggesting that DQ may be biologically active despite its rapid metabolism and lower binding affinity compared to DES. To test this, COS-1 cells were transfected with an estrogen responsive reporter construct containing of VitA2 estrogen response element (ERE) with or without an ER expression vector. In the presence of ER, treatments with DES, DQ and ZZ-DIEN resulted in 11, 10, and 2-fold induction of chloramphenicol acetyltransferase (CAT) activity, respectively. This induction was mediated by estrogen receptor since it was suppressed by pretreatment with a 10-fold excess of the pure antiestrogen ICI 182,780. These data indicate that DQ is a biologically active intermediate that is capable of transactivation of estrogen responsive genes through the ER. Furthermore, the data suggest that the ability of DQ to irreversibly bind ER may result in persistent stimulation of ER. This persistent stimulation may be related to the carcinogenicity of DES.
Steroids 1998 Mar
PMID:Estrogen-dependent gene regulation by an oxidative metabolite of diethylstilbestrol, diethylstilbestrol-4',4"-quinone. 955 16

Estrogen is of vital importance for the development and control of reproductive functions. Until recently, estrogen was believed to regulate complex programs of gene expression by binding to an unique nuclear receptor belonging to the superfamily of ligand-dependent transcription factors. However, the identification of a second estrogen receptor, referred to as ER beta, is leading to a re-evaluation of estrogen signaling and physiology.
Steroids
PMID:Estrogen receptor beta: re-evaluation of estrogen and antiestrogen signaling. 961 97

Estrogen levels in breast tumors of post-menopausal women are as much as 10 times higher than estrogen levels in plasma, presumably due to in situ formation of estrogen. The major source of estrogen in breast cancer cells may be conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Thus, inhibitors of estrone sulfatase have potential for the treatment of estrogen-dependent breast cancers. Several steroidal agents have been developed that are potent estrone sulfatase inhibitors, most notably estrone-3-O-sulfamate. These compounds may have undesired actions, especially estrogenicity. Recently, non-steroidal estrone sulfatase inhibitors have been designed that avoid the problems associated with an active steroid nucleus; however, these have not achieved the potency of estrone-3-O sulfamate. We have designed and synthesized a series of compounds, 17 beta-(N-alkylcarbamoyl)-estra-1,3,5(10)-trien-3-O-sulfamates (6a-d) and 17 beta-(N-alkanoyl)-estra-1,3,5(10)-trien-3-O-sulfamates (11a-d) that combine the structural features of the steroidal estrone sulfatase inhibitors with a membrane insertion region that should increase the affinity for the sulfatase enzyme and decrease the estrogenicity of the steroid. We tested the compounds for estrone sulfatase inhibition by measuring estrone sulfatase activity in intact cultures of human breast cancer cells (MDA-MB-231). We tested for estrogenicity by measuring growth of estrogen-dependent MCF-7 human breast cancer cells. All of the test compounds (10 nM) substantially inhibited estrogen sulfatase activity of intact MDA-MB-231 cells. Dose-response analysis indicated an IC50 of approximately 0.5 nM for two of the compounds (6a and 11a). In the test for estrogenicity, estrone and estrone-3-O-sulfamate significantly stimulated MCF-7 cell growth. In contrast, neither the 17 beta-(N-alkylcarbamoyl)-estra-1,3,5,(10)-trien-3-O-sulfamates++ + nor the 17 beta-(N)-alkanoyl)-estra-1,3,5,(10)-trien-3-O-sulfamates stimulated growth of MCF-7 cells at a concentration of 1 microM, indicating that they are not estrogenic at levels 2000 times greater than their IC50 for estrone sulfatase. Our data indicate the utility of the new compounds for inhibition of breast cancer cell estrone sulfatase activity. Further, our data support the concept that estrone sulfatase inhibitors may be useful as therapeutic agents for estrogen-dependent breast cancers.
Steroids
PMID:Development of potent non-estrogenic estrone sulfatase inhibitors. 965 50

Estrogens and antiestrogens promote specific conformations of the estrogen receptor (ER). To analyze the influence of such configurations on the stability of the ligand-ER complexes, MCF-7 breast cancer cells were exposed for 1 h to either [3H]E2 or an unlabeled estrogen or antiestrogen (E2, DES, E1, BP; OH-Tam, RU 39,411, ICI 164,384, RU 58,668); mutual exchange rates of bound compounds (i.e., [3H]E2-->ligand; ligand-->[3H]E2) were then analyzed in cell extracts by measuring [3H]E2. Addition of cycloheximide (CHX) to the incubation medium eliminated the potential interference of E2-induced ER loss. Extracts from control untreated cells were labeled with [3H]E2 or one of these various ligands and similarly submitted to exchange. Displacement of bound compounds occurred at moderate temperature (18 degrees C) but not at 4 degrees C. Remarkably, exchange proceeded at a lower rate in extracts from cells preincubated with [3H]E2 or a ligand. Antiestrogens RU 39,411 and RU 58,668 appeared especially refractory to displacement. Such low exchange rates were also recorded in experiments conducted on whole cells although to a higher extent than in extracts from preincubated cells. Enzyme immunoassays demonstrated that absence of major exchange could not be attributed to ER loss. Moreover, displacement of bound ligands appeared independent of their binding affinity for the receptor. These data suggest that estrogen and antiestrogen binding is stabilized by at least one factor (coactivators or corepressors) thus fixing the receptor molecules in a configuration that is relatively resistant to subsequent exchange. FPLC and PgR induction revealed that a significant proportion of ER maintained in a sufficiently flexible status was still able to exchange and transduce the transcriptional message of the displacer ligand.
Steroids 1998 Nov
PMID:Exchange of bound estrogens and antiestrogens in MCF-7 cells: evidence for ligand-induced stable configurations of the estrogen receptor. 983 Jun 82


<< Previous 1 2 3 4 5 6 7 8 9 Next >>