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PubMed1983

The absorption, distribution and excretion of anabolic agents.

The metabolic fate of the anabolic agents, diethylstilbestrol, hexestrol, trenbolone acetate, zeranol and the endogenous steroids are discussed under the headings absorption, distribution and excretion. There is an optimum concentration of anabolic agent in the systemic circulation that results in a maximum increase in growth rate of farm animals. This optimum blood concentration should be maintained over a long period. However, there is rapid metabolism and excretion of anabolic agents with short half-lives in blood, and metabolic clearance rate equals entry rate. The rate of absorption of the agent, which is determined by formulation and site of administration, is most important and is best achieved by the use of slow release implants. The pattern of exponential absorption from compressed pellets of single anabolic agents is not ideal, and a more constant payout of drug, in particular estradiol-17 beta, is best achieved in combined preparations of agents or from silicone rubber implants impregnated with the agent. The high metabolic clearance rate and rapid excretion of anabolic substances influences the distribution of residues. Outside the site of administration, less than 1% of the administered dose is present in the animal. The lowest concentrations of residues are found in muscle and fat, higher concentrations are present in liver and kidney and the highest concentrations are in the bile, urine and feces.

Anabolic Agents↗
PubMed2002

[Effects of veterinary drugs on beta-hexosaminidase release from rat basophilic leukemia cells (RBL-2H3)].

Little is known about the effects of residual veterinary drugs on the allergic reaction, except for the antigenicity of antibiotics and synthetic antimicrobials. Therefore, 59 kinds of veterinary drugs were investigated for their effects on the IgE receptor-mediated beta-hexosaminidase release from RBL-2H3 cells as an index of immediate allergic reaction. We found that the antibiotics chlorotetracycline, doxycycline, monensin, the synthetic antimicrobial pyrimethamine and the steroid hormone testosterone inhibited beta-hexosaminidase release. Most of the veterinary drugs showed no action, though the ionophores lasalocid, salinomycin and the steroid hormone hexestrol promoted beta-hexosaminidase release from injured cells. Based on the residual levels of these drugs and the frequencies of detection in actual food samples, it seems unlikely that these drugs have any immediate allergic effect in practice.

Animals↗
PubMed1976

Chemical probes of estrogen action: affinity labeling.

A systemic approach has been taken in the preparation and evaluation of photoaffinity labeling agents for the estrogen receptor from rat and lamb uterus. Several derivatives of estradiol and the nonsteroidal estrogen, hexestrol, containing photoreactive diazocarbonyl or azide functions have been synthesized. The receptor binding affinity of these compounds and their capacity to photointeract with the estrogen binding site (inactivate) can be assayed inderectly by competition assays. Several of the compounds that showed both resonably high binding affinities and inactivation efficiencies have been prepared in high specific activity, tritium-labeled form. Direct binding measurements with these derivatives in unpurified rat uterine receptor preparations, show that while these compounds bind to the receptor, they also show considerable nonspecific binding to nonreceptor proteins. Irradiation of these derivatives in rat uterine cytosol preparations results in incorporation of large amounts of radioactivity into protein in a covalent fashion. The amount of nonspecific labeling is so large, however, that estrogen site specificity (indicated by protection with unlabeled estradiol) cannot be demonstrated. More recently, we have used a partially purified receptor preparation from lamb uterus. The receptor in this preparation has been disaggregated by mild trypsinization and can be electrophoresed in native form. Electrophoretic analysis of the proteins in photolabeled preparations show some covalent incorporation into the receptor region of the gel with one derivative but not with another. The effectiveness of the photoaffinity labeling reagents prepared thus far is assessed, and suggestions are made for the design of new, more effective reagents.

Affinity Labels↗
PubMed1992

Effect of diethylstilbestrol and related compounds on the Ca(2+)-transporting ATPase of sarcoplasmic reticulum.

Diethylstilbestrol is a potent inhibitory agent of the Ca(2+)-ATPase activity of sarcoplasmic reticulum membranes. Other structurally related molecules, such as dienestrol or hexestrol having hydroxyl groups at para positions of the two benzene rings produce similar effects. The absence or derivatization of the hydroxyl groups as occurs with trans-stilbene or diethylstilbestrol dipropionate converts the structure in an activating agent of the enzyme. The Ca2+ transport profiles in the presence of the referred drugs reproduces the same behavior observed for the hydrolytic activity. There is also a clear indication of a membrane-mediated mechanism of these drugs. Ligand binding experiments at equilibrium indicate that diethylstilbestrol decreases the affinity for Ca2+ of the high affinity Ca2+ sites. Functional studies reveal that the activation/inhibition induced by these drugs is correlated with decreased levels of phosphoenzyme at steady state, and these levels are sensitive to the Ca2+ concentration. Chase experiments of [32P]phosphoenzyme and 45Ca2+ indicate a slight activation effect of diethylstilbestrol dipropionate on Ca2+ dissociation during the enzyme turnover. The use of different anthroyloxy derivatives of stearic acid as a fluorescent probe suggest that diethylstilbestrol and other inhibitory agents could be located close to the polar region of the lipid bilayer, which interferes with the Ca(2+)-binding sites, whereas the activators trans-stilbene and diethylstilbestrol dipropionate may have a deeper position into the membrane, which accelerates the Ca2+ translocation process.

Adenosine Triphosphate↗
PubMed2006

[Determination of residues of three stilbene drugs in animal tissues using gas chromatography-mass spectrometry].

A method has been developed to determine residual stilbenes such as diethylstilbestrol (DES), dienestrol (DIS) and hexestrol (HS) in animal tissues using solid phase extraction (SPE) and gas chromatography-mass spectrometry (GC-MS). The procedures for extraction, cleanup on an LC-Si solid phase extraction cartridge and derivatization of stilbenes were established and optimized. The analytes were detected by mass spectrometer with electron impact source in selected ion monitoring mode (EI/SIM), and quantified with an external standard calibration curve method. Linear calibration curves were obtained in the concentration ranges from 5 to 500 microg/L for HS and from 10 to 1000 microg/L for DES and DIS (the correlation coefficients were above 0.99). Recoveries of the stilbenes were 73.0%-86.5%, and the relative standard deviations were between 1.0% and 7.2%. The limits of detection were 0.30 microg/kg for cis-DES, 0.10 microg/kg for trans-DES and HS and 0.15 microg/kg for DIS in pork and swine liver.

Animals↗
PubMed1990

[Sex differences in the accumulation of estrogen receptors in nuclei of liver cells and increase of angiotensinogen concentration in the blood of rats after administration of low doses of synthetic estrogens].

The significance of sex differences in the level of estrogen receptors (ER) in hepatocytes for direct effects of estrogens in male and female rat livers was investigated. 4-5-fold increase in ER level and 20-30%-elevation in plasma angiotensinogen (AG) occurred after a single injection of 0.5 microgram of hexestrol (HE) in female and gonadectomized male rats. In male liver, where the cytosol ER content is two fold lower than that in female rats, nuclear ER level was shown to be very low and unchanged after HE injection, plasma AG also did not change. Injection of 0.5 microgram of ethinylestradiol produced similar effect. Injection of a greater dose of estrogen caused an enhancement in plasma AG level in males. The existence of sex differences in hepatic ER level seems to cause in some conditions different response of metabolic processes in male and female rat liver after estrogenization.

Angiotensinogen↗
PubMed1990

Morphology and anatomic localization of renal microneoplasms and proximal tubule dysplasias induced by four different estrogens in the hamster.

Estrogens are known to induce tumors in high frequency in orchiectomized Syrian golden hamsters, but the histogenesis of the tumors is controversial. In order to identify the earliest precursors of the tumors, animals were implanted with pellets of four different estrogens, sacrificed at times ranging up to 6.4 months, and the various neoplastic and nonneoplastic lesions were characterized. Infiltrating cancers were identified in 80% of animals exposed to diethylstilbestrol, 17 beta-estradiol, and hexestrol for periods of 5.3-6.4 months; however hamsters exposed to ethinyl estradiol for comparable times did not develop any tumors. Proximal tubule dysplasia, identified as focal collections of abnormal-appearing cells with increased [3H]thymidine-labeling indices (eight times higher than nondysplastic cells), was the only nonmalignant change that, for every agent, either preceded or accompanied the development of cancer. The dysplastic lesions were further subdivided into two types when it became apparent that they and carcinoma in situ, another lesion in the proximal tubules, might be part of a continuum of tumor progression that results in infiltrating cancer. Another dysplastic variant, classified as florid dysplasia because of its extensive involvement of tubules, showed well-differentiated features; it was seen only in the ethinyl estradiol-treated hamsters. In a quantitative study of the anatomic localization of dysplasias and microcancers (less than 0.5 mm in diameter) induced by diethylstilbestrol, both lesions showed highest incidence in the deep renal parenchyma. The dysplasias were at least eight times more prevalent in the proximal tubules of the innermost 10% of the cortex and subjacent medulla than in the rest of the cortex. We conclude that proximal tubule dysplasias developing in the deep renal parenchyma are the most likely precursors of the estrogen-induced cancers.

Animals↗
PubMed1989

[Estimation of a direct regulatory effect of estrogens on hepatocytes, evaluated according to the change in the level of free estrogen-binding protein in primary cell culture].

Male rat hepatocyte cultures have been obtained. The culturing hepatocytes had a stable level of some morphological and functional properties. A high level of estrogen receptors (ER) and E2-sensitive unusual estrogen-binding protein (UEBP) was found. A direct dose-dependent inhibiting effect of physiological (10(-10)-10(-7) M) concentrations of E2 on UEBP content was established in cell cultures incubated with the hormone for 3 days. Hexestrol (but not cholesterol) was found to exert a direct inhibiting effect. The inhibiting effect of E2 (10(-9) M) was observed after a 24 hour incubation of hepatocytes with the hormone but was less pronounced. In this case a significant increase in UEBP concentration in hepatocytes was noted 72 hours after the removal of E2. It is concluded that physiological concentrations of E2 can exert a direct regulatory influence on certain functions of culturing hepatocytes acting via hepatocyte ER.

Animals↗
PubMed1987

Interaction of some estrogenic drugs with tubulin. Formation of twisted ribbon structures.

We studied the action of E-diethylstilbestrol (E-DES), erythro-hexestrol (erythro-HES), and E,E-dienestrol (E,E-DIES) on microtubule formation. The three drugs inhibit this formation from microtubular protein; the percentages of inhibition were, respectively, 15% and 45% for 1.25 X 10-s M E-DES and E,E-DIES. With purified tubulin 6S, 7.5 X 10(-6) M E,E-DIES and erythro-HES induced a 20% inhibition. In the case of E-DES, our results are in good agreement with previous ones. These drugs partially disrupt preformed microtubules. Moreover, when E,E-DIES (5 X 10(-5) M) is added to tubulin, loosely organized aggregates composed of twisted ribbon structure are formed. In the case of erythro-HES, similar structures were observed but at higher concentrations. With E-DES, no organized structures are present.

Animals↗
PubMed1983

[Histochemical and biochemical assays of estrogen receptors in breast cancer and significance of endocrine therapy].

Estrogen receptors (ER) in breast cancer patients were determined histologically with estradiol-BSA-FITC and biochemically both by sucrose density gradient and dextran coated charcoal methods. Either 8 S or 4 S ER was found clinically to be related to estrogen dependency. ER-positive cells were in clumps or intermixed with ER-negative cells in cancer tissue, which may be one of the reasons for the fact that surgical ablation of breast cancer patients rarely resulted in complete regression of tumors. High dose administration of Hexestrol of Medroxyprogesterone acetate was occasionally effective for ER-negative human and rat breast cancer, which suggests that there is another endocrinological tumor suppressing mechanism besides the mechanism involving the estrogen-ER system.

Antineoplastic Agents↗
PubMed1984

[Diethylstilbestrol in urine of slaughtered cattle].

The results of an investigation during 1981-1984 for the presence of diethylstilbestrol (DES) in 12576 samples of bovine urine in the Netherlands are presented. The screening was performed by radioimmunochemical detection after chromatographic purification on celite. Subsequent final confirmation was performed by combined high pressure liquid chromatography-gas chromatography mass spectrometry. On the average in 1.7% of the 12576 samples the presence of stilbenes , primarily DES, was proven. Probably due to the reintroduction of the meat inspection act regarding the control for DES, a substantial decrease to 0.2% (4 samples) was observed in the first three months of 1984. In these 4 samples out of 2333 samples the presence of dienestrol (DE) was confirmed. No DES or hexestrol (HEX) could be detected.

Animals↗
PubMed1988

A gas chromatographic/mass spectrometric screening, confirmation, and quantification method for estrogenic compounds.

A method is described for the screening, quantification and confirmation of a variety of estronenic substances in animal tissues. A solid-phase extraction technique combined with a liquid/liquid extraction allows for rapid sample preparation and high throughput for the following compounds in bovine liver, muscle and kidney: diethylstilbestrol, dienestrol, hexestrol, zeranol, taleranol, zearalanone, zearalenone, zearalenol, estradiol and estriol. Gas chromatography/mass spectrometry and selected ion monitoring is used for the determination with detection limits ranging from 50 to 150 ppt.

Animals↗
PubMed1987

Embryotoxicity induced by diethylstilbestrol in vitro.

The embryotoxic potential of diethylstilbestrol (DES) was examined in a whole embryo culture system containing a P-450-dependent bioactivating system. Sprague-Dawley rat embryos were explanted on day 10 and cultured for 24 hours. Concentration-dependent effects of DES on embryonic growth parameters, viability, and embryotoxicity were observed. Concentrations of DES greater than 0.26 mM (final concentration) produced 100% embryolethality, while those below 0.15 mM were without significant effects. At a final concentration of 0.19 mM, DES produced only a slight increase in embryolethality. The same concentration elicited a marked increase in observed embryotoxicity, including prosencephalic hypoplasia, incomplete axial rotation, and open neural tubes. In addition, reductions in embryonic length, somite number, and protein and DNA content were observed. An exogenous P-450-dependent hepatic biotransforming (catechol-generating) system failed to alter either the incidence of observed toxic effects or measured growth parameters. Likewise, exposure of cultured embryos to 20% carbon monoxide (CO) failed to reduce DES-induced embryotoxicity, indicating a lack of participation of an endogenous P-450-dependent embryonic bioactivating system. Arachidonic acid (0.20 mM) and/or indomethacin (0.50 mM) also had no observable effect on DES-induced embryotoxicity, suggesting that prostaglandin synthase was not involved in the embryotoxic activity of DES, as has been proposed to explain its carcinogenic effect. The antioxidants N-acetylcysteine (1.14 mM) and alpha-tocopherol (0.08 mM) failed to protect against DES-induced embryotoxicity, while the anti-estrogen tamoxifen (up to 0.85 mM) actually enhanced this effect of DES in culture. The DES analogs Z,Z-dienestrol (DIES, 0.10 mM) and hexestrol (HES, 0.48 mM) were both embryotoxic in vitro. The presence of an exogenous P-450-dependent hepatic biotransforming system appeared to protect against HES-induced embryolethality but had little effect upon DIES-induced embryotoxicity. The results were consistent with a direct effect of DES independent of either estrogenicity or exogenously generated metabolites.

Animals↗
PubMed1989

Covalent binding to proteins of reactive intermediates resulting from prostaglandin H synthase-catalyzed oxidation of stilbene and steroid estrogens.

Prostaglandin H synthase (PSH) is known to metabolically activate a variety of xenobiotics in vitro by means of its peroxidase activity. Recently, stilbene and steroid estrogens have been found to be cooxidized by ram seminal vesical microsomes, a rich source of PHS, to nonextractable metabolites bound to microsomal protein. To investigate further the nature of this protein binding, different radiolabeled estrogens were incubated with purified PHS, holoenzyme in the presence of various amounts of albumin (BSA), and radioactivity bound to protein was determined after gel electrophoretic separation. Diethylstilbestrol (DES), its analog hexestrol, and the steroid estrogens estrone and 2-hydroxy-estrone were cooxidized by PHS in vitro to metabolites that bound covalently to PHS and to BSA. Although a preferential binding of DES to PHS was found in the presence of excess BSA, reactive intermediates derived from DES, or from the other estrogens, were sufficiently stable to react with the competing nucleophile BSA as well. With respect to the metabolic reactions catalyzed by PHS, in addition to one-electron oxidation of phenolic functions, PHS catalyzed the aromatic hydroxylation of synthetic and steroid estrogens as shown by 3H2O release from regiospecifically labeled compounds and confirmed by product identification. Although DES was extensively metabolized by PHS, its aromatic hydroxylation was minor by comparison to estradiol, a difference possibly related to the compounds' redox potentials. Thus, cooxidation of estrogens in vitro resulted in phenoxy radicals, semiquinones and quinones, reactive intermediates capable of protein binding that may contribute to the adverse effects of stilbene and steroid estrogen observed in vivo and in short-term assays.

Animals↗
PubMed1982

Determination of enviroxime in a variety of biological matrixes by liquid chromatography with electrochemical detection.

A simple and specific method has been developed for determination of enviroxime in biological samples. Enviroxime, a substituted benzimidazole, its coisomer zinviroxime, and the internal standard hexestrol were extracted from the samples with benzene. The benzene layer was evaporated and the residue was reconstituted and injected onto a liquid chromatograph. Reversed-phase chromatography on an octylsilane column with a 65% methanol-35% 0.14 M sodium acetate mobile phase separated the components. The compounds were detected electrochemically using a glassy carbon electrode held at +0.85 V. The assay could detect as little as 4 ng of enviroxime/ml of plasma, 15 ng/ml of nasal wash, and 20 ng/ml of urine or tissue homogenate. For plasma assays, the procedure was greater than 97% accurate and had a relative standard deviation of less than 4%. This method has proven to be applicable and reliable for the determination of enviroxime in many types of biological samples. Several problems encountered during the routine use of electrochemical detection were explored and minimized.

Administration, Oral↗
PubMed1998

Induction of epithelial neoplasms in the ovaries of guinea pigs by estrogenic stimulation.

OBJECTIVE: We have been searching for an animal model for ovarian epithelial neoplasms. Our previous study suggested that by giving intermediate doses of testosterone to guinea pigs it is possible to induce cystadenomas in the ovaries in 6 to 10 months. METHODS: In this study we investigated the effect of different estrogens including estradiol, diethylstilbestrol (DES), estrone, dienestrol, and hexestrol in 24 guinea pigs. Five guinea pigs received sterile water and were used as controls. RESULTS: Bilateral serous cysts were seen in the ovaries of five guinea pigs that received low (0.25 and 0.35 mg) and intermediate (0.5 and 0.7 mg) doses of estradiol for 2 to 9 months. Surface papillary neoplasms were seen in the ovaries of four guinea pigs that received DES at an intermediate dose (6 mg) and high doses (10 and 12 mg) for 3 to 12 months. The ovaries of the other guinea pigs were unremarkable. Estradiol was measured by radioimmunoassay in three guinea pigs. In the serum it ranged from 450 to 580 pg/ml, and in the ovarian cystadenomas it ranged from 1020 to 6575 pg/ml. CONCLUSIONS: (1) It is possible to induce ovarian neoplasms using estrogenic hormones. (2) The best results are obtained with intermediate doses of estradiol and DES. (3) These two hormones induce different lesions: estradiol is associated with cystic lesions and DES with surface papillary tumors. These observations, together with our previous finding that testosterone induces neoplasms with a predominantly glandular pattern, establish the guinea pig as an excellent animal to study ovarian neoplasms, confirm the significance of hormones in the development of ovarian epithelial tumors, and suggest that the different histologic appearance of ovarian epithelial neoplasms might be related to different hormonal effects.

Animals↗
PubMed2002

Initiation of cancer and other diseases by catechol ortho-quinones: a unifying mechanism.

Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases.

Animals↗
PubMed1988

Biochemical mechanism of aminoglycoside-induced inhibition of phosphatidylcholine hydrolysis by lysosomal phospholipases.

Aminoglycosides such as gentamicin are hydrophilic, polycationic drugs which bind to negatively-charged phospholipid bilayers, inhibit the activities of the lysosomal enzymes involved in the degradation of the major phospholipids and cause, in kidney in vivo or in cultured cells, a lysosomal phospholipidosis. In the present study, we show that the hydrolysis of phosphatidylcholine induced in liposomes by lysosomal extracts at pH 5.4 in vitro is critically dependent on the negative charges carried by the bilayer. This hydrolysis, which is predominantly carried on by phospholipases A1 and A2, markedly increases when the phosphatidylinositol content is raised from 10 to 30% of the total phospholipids, i.e. in a range found in natural membranes. Addition of gentamicin decreases the activity of these enzymes in a non-competitive fashion, but the effect is inversely proportional to the amount of phosphatidylinositol present in the bilayer. Gentamicin and bis(beta-diethylaminoethylether)hexestrol (DEH), a cationic amphiphile which also binds to phospholipid bilayers, are equipotent inhibitors when added to negatively-charged liposomes at equinormal concentrations. Although direct aminoglycoside-enzyme interactions cannot be excluded, these results strongly suggest that gentamicin impairs the activities of the lysosomal phospholipases towards phosphatidylcholine by decreasing the available negative charges required for optimal activity.

Aminoglycosides↗