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At least 19 recordsLinked to original sources
PubMed1985

Reactivity of 4',4"-diethylstilbestrol quinone, a metabolic intermediate of diethylstilbestrol.

In a search for the carcinogenic metabolite of diethylstilbestrol, the interactions of 4',4"-diethylstilbestrol quinone with peptides and nucleic acids were investigated. Nonextractable binding of 4',4"-diethylstilbestrol quinone to calf thymus DNA or poly G were observed. However, adduct nucleosides could not be isolated subsequent to enzymatic digestion of nucleic acids. Binding to dGMP or dAMP also occurred, but the initially bound stilbene estrogen could mostly be extracted with 18 extractions using various organic solvents. Non-covalent interactions of 4',4"-diethylstilbestrol quinone with calf thymus DNA were observed spectrally only after exhaustive dialysis of the DNA versus water, but not with native DNA. In chemical reactions of 4',4"-diethylstilbestrol quinone and nucleosides, nucleotides, and amines such as n-pentyl amine, only Z,Z-dienestrol could be identified as reaction product. The quinone did react with mercaptoethanol via Michael addition to the unsaturated carbonyl system to form a stable adduct, 4-(2-hydroxyethylthio)-3,4-di(p-hydroxyphenyl)-2-hexene. It also reacted covalently with sulfur-containing peptides such as reduced glutathione or bovine serum albumin. Partially purified rat liver cytochrome P-450 reductase reduced 4',4"-diethylstilbestrol quinone to E- and Z-diethylstilbestrol. It is proposed that 4',4"-diethylstilbestrol quinone forms unstable adduct intermediates with DNA which decompose with time. Also, covalent binding of 4',4"-diethylstilbestrol quinone to important proteins via thioether linkages may play a role in carcinogenesis.

Amines↗
PubMed1980

Tetrazolium salts in pharmaceutical analysis II: direct assay of diethylstilbestrol and diethylstilbestrol dipropionate.

A convenient spectrophotometric determination of diethylstilbestrol and diethylstilbestrol dipropionate was developed involving their interaction with triphenyltetrazolium chloride at 50 degrees for 45 min and subsequent measurement of the formazan formed. The significance of extended conjugation within t,e 4,4'-stilbenediol molecule to induce the color reaction is documented. Ideal adherence of color absorption to Beer's law permitted accurate and precise determination of diethylstilbestrol and diethylstilbestrol dipropionate pure forms over the range of 2-22 microgram of diethylstilbestrol/ml. Application of the tetrazolium color reaction to the analysis of diethylstilbestrol dipropionate dosage forms was achieved without prior hydrolysis or extraction.

Color↗
PubMed1985

Possible role of 4',4''-diethylstilbestrol quinone in diethylstilbestrol carcinogenesis.

4',4''-Diethylstilbestrol quinone, an intermediate in diethylstilbestrol metabolism, had previously been postulated to play a role in diethylstilbestrol-induced carcinogenesis. Possible mechanisms by which 4',4''-diethylstilbestrol quinone may participate in the induction of tumors by diethylstilbestrol are discussed. The possibilities of a direct modification of cellular macromolecules by the quinone intermediate and also an indirect involvement via generation of radicals are explored.

Biotransformation↗
PubMed1980

Metabolic fate of diethylstilbestrol in the Syrian golden hamster, a susceptible species for diethylstilbestrol carcinogenicity.

1. Diethylstilbestrol, after oral administration to Syrian golden hamsters, is preferentially excreted in the faeces in males, and in about equal amounts in urine and faeces in females. Glucuronides comprise the major urinary conjugate for both sexes. 2. Eleven oxidative metabolites of diethylstilbestrol have been identified in the urinary glucoronide fraction. They represent aliphatic hydroxy-, aromatic hydroxy-, and aromatic methoxy-derivatives of diethylstilbestrol, pseudo diethylstilbestrol, and dienestrol. 3. No sex difference in the oxidative metabolism of diethylstilbestrol was observed in the hamster. 4. Detailed chromatographic and mass spectrometric information on the various metabolites is provided and discussed.

Animals↗
PubMed1991

Elevated 8-hydroxydeoxyguanosine levels in DNA of diethylstilbestrol-treated Syrian hamsters: covalent DNA damage by free radicals generated by redox cycling of diethylstilbestrol.

The generation of free radicals by microsome-mediated redox cycling between catechol estrogens or diethylstilbestrol and their corresponding quinones has previously been demonstrated in vitro. However, the reaction of free radicals with DNA has not yet been detected in animals treated with estrogen and is the subject of this investigation. The reaction of guanine bases of DNA with hydroxyl radicals to form 8-hydroxydeoxyguanosine has been used as a monitor of free radical generation in kidney and liver of Syrian hamsters, a species prone to estrogen-induced carcinogenesis. Prior to in vivo measurements, the in vitro hydroxylation of guanine bases of DNA under conditions of redox cycling of estrogen was investigated. In incubations of DNA or deoxyguanosine with hamster kidney microsomes, NADPH, and diethylstilbestrol 4',4"-quinone, the hydroxylation of guanine bases of free deoxyguanosine or of DNA was 50 to 100% higher than in controls. When incubations were carried out in the presence of iron(III) chloride, the hydroxylation of guanine bases was 2.5- or 10-fold higher than control values. There was a 65% increase from control values in levels of 8-hydroxydeoxyguanosine in liver DNA of hamsters treated with 20 mg/kg/day diethylstilbestrol for 3 days and 100 mg/kg on the 4th day. In hamsters treated chronically with diethylstilbestrol implants for 15 days, 8-hydroxydeoxyguanosine levels more than doubled from control values in kidney but not liver DNA. Treatment of hamsters with estradiol for various time periods did not induce any changes in levels of hydroxylated guanine in either kidney or liver. It was concluded that in vitro and in vivo redox cycling of diethylstilbestrol hydroxylated guanine bases in DNA.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1975

The stimulatory effects of diethylstilbestrol and diethylstilbestrol diphosphate on the reticuloendothelial cells of the rat spleen.

The effects of the estrogenic compounds, diethylstilbestrol (DS) and diethylstilbestrol dophosphate (DSP) on morphologically demonstrable characteristics of reticuloendothelial (RE) cells were studied in rat spleen. These included metalophilia, acid phosphatase, nonspecific esterase and phagocytosis. Routine histological and histochemical techniques were used to determine the distribution of metalophilic cells, hydrolytic enzymes, the presence of intracytoplasmic PAS-positive material, hemosiderin sequestration, and the ability to phagocytose injected carbon particles and bacterial organisms. Changes in these parameters associated with increased RE function were observed in several regions of spleens of DS or DSP-treated animals. The marginal metalophils at the periphery of the nodule, normally not phagocytic in animals of the age studied, became phagocytic and demonstrated increased metalophilic and enzymatic activity. The red pulp was characterized by increased densities of cells in pulp cords demonstrating metalophilia, hydrolytic enzyme activity, PAS positivity and hemosiderin. Phagocytosed material was limited to cells in the pulp cord. The reactions of the sinus-lining cells were not affected by this treatment. Results indicated that the marginal metalophils have the capacity to become fully functional RE cells under the influence of these drugs.

Acid Phosphatase↗
PubMed1998

Estrogen-dependent gene regulation by an oxidative metabolite of diethylstilbestrol, diethylstilbestrol-4',4"-quinone.

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.

Animals↗
PubMed1989

Metabolic oxidation of diethylstilbestrol to diethylstilbestrol-4',4"-quinone in Syrian hamsters.

Diethylstilbestrol-4',4"-quinone (DES Q) has previously been postulated to be a reactive intermediate in diethylstilbestrol (DES) metabolism. DES is oxidized to DES Q in vitro, but the occurrence of the quinone metabolite in vivo has not yet been demonstrated due to its instability and chemical reactivity. In this report, the characteristics of in vitro formation of DES Q and the isolation of 3H-labeled DES Q from tissue extracts of hamsters injected with radiolabeled DES is described. In vitro, the time-dependent formation of DES Q as a function of microsomal protein, cofactor or substrate concentrations was demonstrated. The microsome-mediated oxidation of DES to quinone was inhibited by various compounds that also effectively inhibit the peroxidatic activity of cytochrome P-450. In vivo, the formation of DES Q occurred in all tissues investigated, livers and kidneys of male and female adult hamsters, neonates and fetuses, and in uterus and placenta. Concentrations of quinone metabolite in liver and kidney of adult hamsters after injection of 75 mumol/kg DES were 76 and 20 pmol/g tissue respectively. In neonates and fetus, concentrations of DES Q after the same dose of DES were markedly less than those in adults (0.026 and 0.047% of adult levels in neonatal liver and kidney and 0.013 and 0.016% of adult levels in fetal liver and kidney respectively). Since DES Q was also formed by fetal liver homogenate in vitro, fetal oxidizing enzymes appear to be the source of the quinone metabolite in this tissue. DES Q concentrations were also examined after injection of DES into hamsters pretreated with vitamin C or alpha-naphthoflavone, substances known to inhibit DES-induced renal carcinogenesis. Quinone metabolite levels were cut in half in response to vitamin C in correlation with the approximately 50% decrease in DES-induced renal tumors reported previously. alpha-Naphthoflavone pretreatment decreased renal and hepatic DES Q concentrations by 70 and 17% respectively, also in correlation with the known prevention of kidney tumors by this flavone. These data support a role of DES Q in DES-induced carcinogenesis. Since there is no correlation between DES Q concentrations and target site specificity of DES induced tumors, the oxidation of DES to DES Q and the genotoxicity of this metabolite may be a necessary but not sufficient event in tumor development. Hormone-dependent growth of initiated cells may also be necessary for the occurrence of cancers.

Aging↗
PubMed1984

Increased incidence of cervical and vaginal dysplasia in 3,980 diethylstilbestrol-exposed young women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project.

The incidence rates of dysplasia and carcinoma in situ (CIS) of the cervix and vagina were determined in 3,980 young women exposed prenatally to diethylstilbestrol. Strict criteria were developed to minimize selection bias among the subset of 744 pairs of matched exposed and unexposed (control) cohort participants, all of whom were identified through review of prenatal obstetrical records. A high degree of compliance was achieved throughout the seven-year study period since in each group about 90% of the women remained as active participants, kept 77% of the annual anniversary examinations, and had separate Papanicolaou smears of the cervix and vagina performed in 99% of the anniversary examinations. The incidence rate for dysplasia and CIS was significantly higher in the women exposed to diethylstilbestrol than in those not exposed in the matched cohort (15.7 v 7.9 cases per 1,000 person-years of follow-up). The rates were higher in the exposed women if squamous metaplasia extended to the outer half of the cervix or onto the vagina. In other respects, the matched cohorts were strikingly similar.

Adult↗
PubMed1988

A comparison of diethylstilbestrol or orchiectomy with buserelin and with methotrexate plus diethylstilbestrol or orchiectomy in newly diagnosed patients with clinical stage D2 cancer of the prostate.

From April 1983 to March 1985, 265 patients with newly diagnosed metastatic prostate cancer were randomized to one of three treatment protocols: (1) diethylstilbestrol (DES) or bilateral orchiectomy, (2) the leutinizing hormone-releasing hormone (LHRH) analog buserelin, or (3) methotrexate plus DES or orchiectomy. In 261 evaluable patients there was no significant difference in survival between the three groups. However, progression-free survival (PFS) was significantly different (P less than 0.0005, log-rank test). Of the possible pairwise comparisons for PFS, two showed significance; buserelin was inferior to DES/orchiectomy (P less than 0.05) and buserelin was inferior to methotrexate plus DES/orchiectomy (P less than 0.0001).

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Neonatal coadministration of testosterone with diethylstilbestrol prevents diethylstilbestrol induction of most reproductive tract abnormalities in male rats.

The primary purpose of this study was to evaluate whether the coadministration of testosterone (TE; 200 micro g) with 10 micro g of diethylstilbestrol (DES) between days 2 and 12 postnatally could prevent the adverse gross reproductive tract changes and associated loss of androgen receptor (AR) expression induced by DES treatment alone. Various endpoints (rete testis area, efferent duct lumen area, epithelial cell height of efferent ducts, and vas deferens) were quantified to check for the abnormal changes that have been shown to occur after neonatal treatment with a high dose (10 micro g) of DES. Additionally, DES induction of an aberrant pattern of estrogen receptor alpha (ER-alpha) immunoexpression in the vas deferens and seminal vesicles was evaluated. The coadministration of DES with TE prevented the induction of all but one of the abnormalities induced by DES treatment on its own, coincident with the restoration of normal/supranormal TE levels and normal immunoexpression of the AR and ER-alpha in the tissues studied. The exception was DES-induced lumenal distension of the efferent ducts, which was only partially prevented by the coadministration of DES with TE. These evaluations were made on day 18, but the described abnormalities were already somewhat evident by day 8 in DES-treated animals. It was therefore tested whether a delay of TE replacement until days 8-12 was still able to reverse the abnormalities already induced by DES treatment alone. A delayed treatment with TE reversed the adverse changes in epithelial cell height and in ER-alpha and AR immunoexpression in the same tissues by day 18; however, rete testis overgrowth was only partially prevented, and efferent duct distension was not prevented at all. These results provide further evidence that DES-induced disorders of reproductive tract development in the male result from a disturbance of the androgen-estrogen balance rather than from estrogen action alone.

Androgens↗
PubMed1988

Effect of pretreatment with 7,8-benzoflavone and diethylstilbestrol on the hepatic metabolism of diethylstilbestrol in the male Syrian golden hamster in vivo.

Liver tumors are induced in male Syrian golden hamsters by the combined treatment with diethylstilbestrol (DES) and 7,8-benzoflavone (7,8-BF), but not with either substance alone. With the aim of clarifying whether metabolic activation of DES is involved in the mechanism of tumorigenesis in this animal model, we have studied the effect of pretreatment with 7,8-BF alone, DES alone, and 7,8-BF plus DES for 2, 8, 20 and 32 weeks on the hepatic in vivo metabolism of DES, using biliary metabolites collected from bile-duct cannulated male hamsters as probe. Formation of glucuronides and sulfates was not affected by treatment with 7,8-BF nor 7,8-BF plus DES. In contrast, animals pretreated with DES alone had a decreased amount of glucuronides and an increased proportion of unconjugated material in the bile. Oxidative metabolism of DES was not significantly altered in hamsters treated with 7,8-BF for up to 20 weeks, whereas pretreatment with DES alone and with 7,8-BF plus DES caused an enhancement of oxidative DES metabolism in vivo, leading mostly to highly polar, as yet unidentified products. From a consideration of various cytochrome P-450-associated enzyme activities, it is concluded that the observed effect on biliary DES metabolites is most likely to be due to an estrogen-induced intrahepatic cholestasis. Taken together, the data do not support a role for the metabolic activation of DES in this tumor model. Alternative mechanisms are proposed.

Animals↗
PubMed1988

Effect of pretreatment of male Syrian golden hamsters with 7,8-benzoflavone and with diethylstilbestrol on P-450 isoenzyme activities and on microsomal diethylstilbestrol metabolism.

Combined treatment of male Syrian golden hamsters with the synthetic estrogen diethylstilbestrol (DES) and 7,8-benzoflavone (7,8-BF) gives rise to a high incidence of hepatocellular carcinomas, whereas no such tumors are formed with DES alone nor with 7,8-BF alone. To determine whether alterations in DES metabolism may account for the observed hepatocarcinogenicity, we have studied the effect of pretreatment with 7,8-BF alone, DES alone and 7,8-BF plus DES on the levels of hepatic P-450 and cytochrome b5, on the activities of various P-450 isoenzymes and on microsomal DES metabolism. Hepatic P-450 content was significantly increased after pretreatment with 7,8-BF and decreased after DES, while combined pretreatment led to levels similar to those in untreated control animals. Hepatic cytochrome b5 was also elevated in 7,8-BF-treated hamsters; DES pretreatment had no effect, and combined pretreatment led to a slight increase. Four different substrates were used to probe P-450 isoenzyme activity. Aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin-O-deethylase (ECOD), 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) were all elevated after 7,8-BF-pretreatment, while DES led to a decrease in these activities with the exception of AHH, where a transient increase which was observed after 8 and 20 weeks of pretreatment was back to control levels after 32 weeks. Combined pretreatment with 7,8-BF and DES led to an intermediate response (slight increase) with AHH, EROD and PROD, but not with ECOD, where a full induction comparable with that observed after 7,8-BF alone was elicited. In spite of the modulation of enzyme levels and activities observed after the various pretreatments, the metabolism of DES in microsomes from pretreated animals was virtually identical with that from controls. Therefore it is concluded that modulation of hepatic DES metabolism is not the reason for the observed hepatotumorigenicity; instead, it is speculated that 7,8-BF is the carcinogenic agent in this tumor model, and DES may act as a promotor.

Animals↗
PubMed1995

Temporal and spatial factors in diethylstilbestrol-induced squamous metaplasia in the developing human prostate. II. Persistent changes after removal of diethylstilbestrol.

To determine if the metaplastic effects of diethylstilbestrol (DES) on prostatic development are reversible, human fetal prostates (obtained from abortus specimens 6-22 weeks old) were bisected mid-sagittally; one half was grafted under the renal capsule of untreated, athymic, male nude mice and the contralateral half was similarly grafted into DES-treated hosts. Severe squamous metaplasia seen in the prostatic ducts after 1 month of continuous DES exposure either disappeared entirely or became reduced in extent and degree after retransplantation of the DES-treated specimens to untreated, intact male hosts and 2 additional months of growth. However, 14 of 21 DES-treated prostates harvested after a 2-month recovery period without DES revealed ductal dilatation (ectasia) and persistent distortion of ductal architecture. Ectasia was most severe in the proximal ducts near the urethra and in prostates 17 weeks or older at the end of 1 month of DES treatment. The clinical consequences of early alteration of prostatic ductal architecture and development are potentially deleterious, as men who were prenatally exposed to DES may be at increased risk for the development of prostatic disease.

Animals↗
PubMedDate not supplied

Effects of postpubertal treatment with diethylstilbestrol and tamoxifen on protein expression in the vagina and uterus of neonatally diethylstilbestrol-exposed mice.

Postpubertal injections of a synthetic estrogen, diethylstilbestrol (-DES), and an anti-estrogen, tamoxifen (-Tx), stimulate proliferation of vaginal and uterine epithelial cells of ovariectomized (OVX) adult mice. In vaginae of two groups of OVX mice treated neonatally with DES (DES-) and oil vehicle alone (Oil-), postpubertal injections of DES altered all and 25 out of 37 protein expressions examined, except for keratin polypeptides, respectively. Twenty-one of the DES- and Tx-altered protein expressions showed the same behavior, suggesting that Tx acts as an estrogen agonist on these proteins. Both neonatally Oil- and DES-treated OVX mice given postpubertal injections of DES (Oil-DES and DES-DES) and Tx (Oil-Tx and DES-Tx) showed similar histological changes in the vagina. Epithelial proliferation and superficial cornification were observed in vaginae of five groups of Oil-DES, Oil-Tx, DES-DES, DES-Tx and DES-Oil (given oil postpubertally) OVX mice. In these groups, 13 proteins showed the same behavior, implying that these proteins are related to proliferation and cornification of mouse vagina. The histology of the uterus in DES-Oil OVX mice closely resembled that in Oil-Oil OVX mice; in protein expressions of the uterus, 5 proteins in DES-DES and 7 proteins in DES-Tx OVX mice were different from those in Oil-DES and Oil-Tx OVX mice, respectively. These findings indicate that neonatal DES treatment alters the behavior of the vagina and uterus in response to postpubertally administered DES and Tx.

Animals↗
PubMed1977

Effect of diethylstilbestrol on the cell kinetics of subcutaneous growth of diethylstilbestrol-induced renal carcinoma.

A response to diethylstilbestrol (DES) of DES-induced renal carcinoma in Syrian hamster was studied by comparing subcutaneous growth of this tumor in DES-treated and untreated animals with respect to the growth curve, cell cycle time, Tc, growth fraction, GF, and cell loss factor, phi. In both conditions the tumor growth followed the Gompertz curve, but the latent period was 14 days longer without DES than with DES. In the untreated animals, Tc was 80% longer due to increases of TGl and TS. However, phi was not changed significantly and GF rather increased without DES. It was concluded that DES-dependency of this tumor growth was manifested in the prolongation of Tc.

Animals↗
PubMed1981

Isomerization of trans-diethylstilbestrol to pseudo-diethylstilbestrol.

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.

Diethylstilbestrol↗