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At least 325 records · Page 18Linked to original sources
PubMed1985

Diethylaminoethoxyhexestrol causes hypertriglyceridemia in guinea pigs.

Treatment of rats, monkeys and man with diethylaminoethoxyhexestrol causes phospholipid storage in liver and other tissues. However, this drug has not been reported to alter plasma lipoprotein levels. When guinea pigs were treated with diethylaminoethoxyhexestrol, the fasting plasma triacylglycerol levels increased dramatically, from 43 to 1281 mg/dl, after only five doses of 12.5 mg/kg. Diethylaminoethoxyhexestrol-treated guinea pigs had reduced postheparin lipase activity. In addition, in vitro assays showed that this agent inhibited guinea pig postheparin lipoprotein lipase. It is hypothesized that diethylaminoethoxyhexestrol causes hypertriglyceridemia in guinea pigs because these animals are known to have low levels of serum activator for lipoprotein lipase and may be unusually susceptible to agents that inhibit lipoprotein lipase activity. The ability to produce hypertriglyceridemia in guinea pigs provides an animal model in which the metabolic consequences of hypertriglyceridemia can be studied.

Animals↗
PubMed1978

Estrogen withdrawal in chick oviduct. Characterization of RNA synthesized in isolated nuclei using a mercurated precursor.

1. As a prerequisite for analyzing the effect of estrogen on transcription in chick oviduct, we describe suitable methods for the synthesis (under conditions restricting reinitiation), and isolation of RNA transcripts from oviduct nuclei in vitro, utilizing mercurated UTP (Hg-UTP) as an RNA precursor and chromatography on sulphydryl-Sepharose (SH-Sepharose) to recover mercurated RNA (Hg-RNA). The techniques described include treatment of Hg-RNA with p-hydroxymercuribenzoate, to improve the efficiency of binding to SH-Sepharose, and elution of Hg-RNA from SH-Sepharose after treatment with 60% formamide at 90 degrees C, to eliminate contamination by aggregated nucleic acid. 2. RNA synthesized by endogenous form B RNA polymerase (using either UTP or Hg-UTP as precursor) was recovered in nuclear lysates in the form of 30--85-S heterogeneous RNA . protein complexes, and after removal of protein, was 10--12 S in size. 3. The nature of RNA transcripts synthesized in vitro was examined by hybridization. More than 90% of the RNA was complementary to "unique" DNA sequences, and 50--60% of the hybridized RNA could be competed with homologous, steady-state nuclear RNA, indicating a significant degree with homologous, steady-state nuclear RNA, indicating a significant degree of homology between in vitro transcripts and in vivo RNA. The level of homology was similar whether RNA synthesis was performed in low salt, or in high salt in the presence of heparin. Possible reasons for only partial competition in these experiments are discussed. 4. Withdrawal of estrogen from chicks leads to a 50% reduction in endogenous RNA polymerase activities in nuclei within 48 h. Similar levels of competition with Hg-RNA transcripts for "unique" DNA were obtained using oviduct nuclear RNAs isolated before or after estrogen withdrawal, and even with liver nuclear RNA. Thus, in oviduct, those sequences present in primary transcripts, and analyzed under our experimental conditions, are present in different hormonal states and also in other chick tissues.

Amanitins↗
PubMed1988

Inhibition of the H+-ATPase in bovine adrenal chromaffin granule ghosts by diethylstilbestrol. Evidence for a tight coupling between ATP hydrolysis and proton translocation.

Diethylstilbestrol (DES) was found to inhibit reversibly the hydrolysis of MgATP (80% at 100 microM) and proton pump activity (I50 approximately equal to 15 microM, complete at 100 microM) in chromaffin granule ghosts. The parallel inhibition suggests a tight kinetic coupling between the two activities. The Mg2+-ATPase activity, but not proton pumping, was partially restored by N,N'-dicyclohexylcarbodiimide, indicating that the two inhibitors in combination cause a partial uncoupling. The non-competitive type of inhibition shows that the action of DES is distal to the site of ATP binding and hydrolysis. Although unspecific, the interaction of DES with the chromaffin granule membrane seems primarily to affect the H+-ATPase.

Adenosine Triphosphate↗
PubMed1993

Carcinogenic antioxidants. Diethylstilboestrol, hexoestrol and 17 alpha-ethynyloestradiol.

The synthetic oestrogens diethylstilboestrol, hexoestrol and 17 alpha-ethynyloestradiol are known to be carcinogenic, yet they all exert antioxidant properties in vitro in that they are good inhibitors of iron ion-dependent lipid peroxidation. In rat liver microsomes incubated with Fe(III)-ascorbate or Fe(III)-ADP/NADPH and also in ox-brain phospholipid liposomes incubated with Fe(III)-ascorbate; the overall order of effectiveness of the compounds tested as inhibitors of lipid peroxidation was diethylstilboestrol > hexoestrol > 17 alpha-ethynyloestradiol > 4-hydroxytamoxifen > 17 beta-oestradiol > tamoxifen. Compounds acting as antioxidants towards lipids may also exert pro-oxidant effects towards other molecules such as DNA and thus must never be assumed to be safe for human use.

Animals↗
PubMed1982

[Steroid ligands of androgen binding protein. The enantiomers of trans-trans and cis-trans perhydrohexestrols and trans-trans perhydrodiketones].

In the framework of a study on nonsteroidal androgens, the authors previously observed that in perhydrohexestrol series, the (+/-)-[(cis-4 hydroxycyclohexyl)-4(trans-4 hydroxycyclohexyl)-hexane] or cis-trans perhydrohexestrol and especially the (+/-)-(3,4 bis (trans-4-oxocyclohexyl)-hexane) or trans-trans perhydrodiketone, there is no affinity for AR (androgen receptor of the prostate) but they bind with high and specific affinity to the testosterone binding sites on ABP (epididymal androgen-binding protein). In this work, we describe the preparation, the stereochemistry and biological activities of trans-trans and cis-trans perhydrohexestrols and of trans-trans perhydrodiketone as well as their corresponding enantiomers. Biologically the tests AR and ABP are negative for the trans-trans perhydrohexestrol and of trans-trans perhydrodiketone and for its enantiomers. However for the enantiomers of cis-trans perhydrohexestrol and of trans-trans perhydrodiketone, the affinity of the (+) enantiomer for ABP is superior to that of the racemic and that of the (-) enantiomer, whereas the affinity for AR are zero. Chemically, the stereochemistry of the three racemics has been established by X-ray crystallographic analysis or by 1H n.m.r. The n.m.r. spectra have been analyzed in terms of chemical shifts and coupling constants.

Androgen-Binding Protein↗
PubMed1988

Characteristics of estrogen-2/4-hydroxylase in pig blastocysts: inhibition by steroidal and nonsteroidal agents.

The inhibitory potencies of steroidal and non-steroidal estrogens, catechol-estrogens, methoxyestrogen, haloestrogens, cholesterol and its side-chain-cleaved products, and inhibitors of steroid aromatase against the activity of estradiol-2/4-hydroxylase (E-2/4-H) in pig blastocysts were studied. All tested compounds, except cholesterol and 4-hydroxyandrostenedione, inhibited E-2/4-H in vitro. The fluctuation of E-2/4-H activity in pig blastocysts on different days of pregnancy may be due to the modulation of enzyme activity by steroids in the uterine lumen. Although alpha-naphthoflavone and aminoglutethimide did not affect E-2/4-H activity in vitro, inhibition by CO (95% CO + 5% O2), SKF-525A, piperonyl butoxide, and antibody to cytochrome P-450 reductase provides evidence for the involvement of cytochrome P-450 in E-2/4-H activity in pig blastocysts.

Animals↗
PubMed1989

Receptor binding of NBD-labeled fluorescent estrogens and progestins in whole cells and cell-free preparations.

We have studied the interactions of four fluorescent steroid conjugates with either the estrogen or progesterone receptor, both in whole cells and cell-free receptor preparations. The fluorophore, nitrobenzoxadiazole (NBD), was conjugated with a synthetic progestin, with a steroidal estrogen, a non-steroidal estrogen, and with an antiestrogen. With all compounds, receptor-specific binding could be detected by fluorescence measurements following extraction from the protein into an organic solvent. In the native state, however, the NBD-ligand-receptor complex is essentially non-emissive, although these ligands fluoresce strongly when associated with non-specific binders such as albumin. The binding site concentrations and relative affinities determined by fluorescence (after extraction) correspond well with those determined by [3H]estradiol or [3H]R5020 binding to their respective receptors. In T47D breast cancer cells, the NBD-progestin showed receptor-mediated uptake and nuclear localization. These compounds have provided valuable information about the interactions of low and medium affinity ligands with their receptors; however, the successful use of fluorescent ligands for detecting steroid receptors under native-bound conditions, by "imaging" modalities (fluorescence microscopy and flow cytometry) will require the development of fluorophores that are emissive while receptor bound or assay protocols that enable the environment of ligands associated with the receptor to be controlled.

Affinity Labels↗
PubMed1989

Inhibition of 17 alpha-hydroxylase/C17-C20 lyase by bifluranol and its analogues.

A simple assay for the measurement of the activities of both 17 alpha-hydroxylase and C17-C20 lyase is described. No extraction procedures are required. The separation of substrate and products is achieved using HPLC which allows the collection of the components of interest and the monitoring of the recovery of various steroids. Using this assay, bifluranol (known to show anti-prostatic activity in vivo) and some analogues were tested for inhibitory activity towards these enzyme activities. Each compound was active, although less potent than ketoconazole, and this activity may contribute towards the in vivo action.

Animals↗