In vitro metabolism of diethylstilbestrol by hepatic, renal and uterine microsomes of rats and hamsters

Haaf, Heidemarie; Metzler, Manfred

doi:10.1016/0006-2952(85)90155-8

Cited by 31 publications

(14 citation statements)

References 8 publications

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“…The major metabolite of hexestrol and DES is their catechol (51)(52)(53)(54), which can be metabolically converted to their catechol quinone. This hexestrol quinone has chemical and biochemical properties similar to those of CE-3,4-Q, i.e., it specifically forms an N7Gua adduct after reaction with dG or DNA (55).…”

Section: Catechol Estrogen-34-quinones and Apurinic Sites In Cancer mentioning

confidence: 99%

Chapter 4: Estrogens as Endogenous Genotoxic Agents--DNA Adducts and Mutations

Cavalieri¹,

Frenkel²,

Liehr³

et al. 2000

JNCI Monographs

523

412

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Section: Catechol Estrogen-34-quinones and Apurinic Sites In Cancer mentioning

confidence: 99%

Chapter 4: Estrogens as Endogenous Genotoxic Agents--DNA Adducts and Mutations

Cavalieri¹,

Frenkel²,

Liehr³

et al. 2000

JNCI Monographs

523

412

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“…Monooxygenases from various sources (Tsutsui et al 1984;Haaf and Metzler 1985;Degen et al 1990), including ram liver microsomes (Foth and Degen; unpublished), catalyze DES hydroxylation. Although these enzymes can oxidize DES also to Z,Z-DIES, the absence of hydroxylated DES metabolites speaks against MFO activity in SEMV cells.…”

Section: Modulation Of Des Metabolismmentioning

confidence: 97%

Prostaglandin H synthase dependent metabolism of diethylstilbestrol by ram seminal vesicle cell cultures

Foth

Degen

1991

Arch Toxicol

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Prostaglandin H synthase (PHS) peroxidase dependent metabolic activation has been suggested to play a role in mediating adverse effects of various carcinogens. Recently, we derived a cell line from ram seminal vesicles (SEMV cells) to conduct studies on the PHS-mediated metabolism of estrogens and xenobiotics in intact cells with the goal of relating this to an endpoint for genotoxicity inducible in this in vitro model. The present paper describes the drug-metabolizing capability of SEMV cells which has been investigated using radiolabeled diethylstilbestrol (DES) and analysing culture extracts by means of reverse phase HPLC with on-line radioactivity detection and after enzymatic hydrolysis of conjugate fractions. The synthetic estrogen DES is converted to sulfate conjugates and to the oxidative metabolite Z,Z-dienestrol (Z,Z-DIES) in a time-dependent manner. Compounds expected to modulate PHS-dependent co-oxidation of DES increased (arachidonic acid) or inhibited (indomethacin) Z,Z-DIES formation of SEMV cells in culture. A comparison of rates of arachidonic acid turnover to prostaglandins on the one hand and DES oxidation on the other reveals that DES is oxidized despite the presence of competing endogenous cosubstrates of PHS peroxidase. The results clearly indicate that SEMV cells catalyze PHS-dependent oxidation of DES as well as carrying out phase II metabolism in the absence of detectable monooxygenase activity. These features and recent data showing that DES can induce micronuclei in SEMV cells makes them an attractive model for further investigations of the role of PHS in mediating the genotoxicity of DES and other xenobiotics.

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“…These two compounds, similarly to the endogenous estrogens, are carcinogenic in the kidney of Syrian golden hamsters [73,74], and the major metabolites are their catechols [74][75][76][77]. These catechols can be easily oxidized to catechol quinones.…”

Section: Unifying Mechanism Of Tumor Initiation By Synthetic Estrogensmentioning

confidence: 99%

Estrogen-Induced Depurination of DNA: A Novel Target for Breast Cancer Prevention

Cavalieri¹

2007

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE 01-05-20072. REPORT TYPE Annual DATES COVERED7 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERUniversity of Nebraska Medical Center Omaha, NE 68198-6805 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTESOriginal contains colored plates: ALL DTIC reproductions will be in black and white. ABSTRACTThe research conducted in this COE grant is based on the paradigm that estrogens can become endogenous carcinogens when their metabolism is unbalanced, favoring formation of catechol estrogen quinones and their reaction with DNA. Compelling evidence obtained in the various specific aims of this COE will be decisive for determining the risk of breast cancer by using the depurinating estrogen-DNA adducts as biomarkers. These biomarkers will also be used for evaluating the ability of specific antioxidants to prevent breast cancer initiation. Much of the research accomplished by this COE was published in a review article in BBA-Reviews in Cancer, which was co-authored by all the participants of the COE. .................................................................................................... 93 Body.......................................................................................................................... SUMMARY OF OVERALL DISCOVERIESThe research conducted in this COE grant was based on the paradigm that estrogens can become endogenous carcinogens when their metabolism is unbalanced, favoring formation of catechol estrogen quinones and their reaction with DNA [1]. The further evidence obtained in the various specific aims of this COE will be decisive for determining the risk of breast cancer by using the depurinating estrogen-DNA adducts as biomarkers. These biomarkers will also be used for evaluating the ability of specific antioxidants to prevent breast cancer initiation.Much of t...

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In vitro metabolism of diethylstilbestrol by hepatic, renal and uterine microsomes of rats and hamsters

Cited by 31 publications

References 8 publications

Chapter 4: Estrogens as Endogenous Genotoxic Agents--DNA Adducts and Mutations

Chapter 4: Estrogens as Endogenous Genotoxic Agents--DNA Adducts and Mutations

Prostaglandin H synthase dependent metabolism of diethylstilbestrol by ram seminal vesicle cell cultures

Estrogen-Induced Depurination of DNA: A Novel Target for Breast Cancer Prevention

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