Slow loss of deoxyribose from the N7deoxyguanosine adducts of estradiol-3,4-quinone and hexestrol-3′,4′-quinone.

Saeed, Muhammad; Zahid, Muhammad; Gunselman, Sandra J.; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.1016/j.steroids.2004.09.011

Cited by 35 publications

(43 citation statements)

References 12 publications

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“…Evidence from the studies performed with estrogens as well as polycyclic aromatic hydrocarbon (PAH)-DNA adducts suggests that depurinating adducts play a major role in tumor initiation compared to stable adducts (83). Furthermore, only the N3-Ade adduct is likely to induce mutations since this adduct depurinates instantaneously, whereas the N7-Gua adduct takes hours to hydrolyze (84). Quinones from the 4-OHE1/E2 (4-OHE1/E2-o-quinone; Fig.…”

Section: Genotoxic Effects Via Oxidative Estrogen Me-tabolismmentioning

confidence: 99%

Dual roles of estrogen metabolism in mammary carcinogenesis

Chang

2011

BMB Reports

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A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review. [BMB reports 2011; 44(7): 423-434]

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Section: Genotoxic Effects Via Oxidative Estrogen Me-tabolismmentioning

confidence: 99%

Dual roles of estrogen metabolism in mammary carcinogenesis

Chang

2011

BMB Reports

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“…This finding may result from the instantaneous depurination of the 4-OHE 1 (E 2 )-1-N3Ade adducts and much slower depurination of the 4-OHE 1 (E 2 )-1-N7Gua adducts (9,10). The rapid depurination of the N3Ade adducts may favor error-prone repair of the apurinic sites and generation of mutations, while the slower depurination of N7Gua adducts may allow error-free repair of the DNA.…”

Section: Mutagenicity Of Estrogensmentioning

confidence: 99%

“…1). This mechanism of metabolic activation can occur with benzene (2,3), naphthalene (4,5), the natural estrogens estrone (E 1 ) and estradiol (E 2 ) (6-9) and the synthetic estrogens hexestrol (10,11) and diethylstilbestrol (DES) (Figure 2) (12). The apurinic sites formed by loss of these adducts from DNA can generate the critical mutations leading to the initiation of cancer (13)(14)(15).…”

mentioning

confidence: 99%

Oxidative Stress in the Metabolism of Estrogens Leading to Cancer Initiation: Prevention by Specific Antioxidants

Rogan

Cavalieri

2011

ACS Symposium Series

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Oxidative metabolism of the estrogens estrone (E 1 ) and estradiol (E 2 ) is the critical event in the initiation of cancer by estrogens. E 1 and E 2 are oxidized by cytochrome P450 (CYP) to the catechol estrogens 2-OHE 1 (E 2 ) and 4-OHE 1 (E 2 ) and then to the catechol estrogen quinones, which react with DNA to form estrogen-DNA adducts. The E 1 (E 2 )-3,4-quinones [E 1 (E 2 )-3,4-Q] react predominantly with DNA to form the depurinating adducts 4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua. The resulting apurinic sites in the DNA can generate mutations leading to the initiation of cancer. Estrogen metabolism becomes unbalanced when expression of the activating enzymes CYP19 (aromatase) and CYP1B1 is higher and expression of the protective enzymes catechol-O-methyltransferase and quinone reductase is lower. In this case, larger amounts of adducts are formed, and the risk of initiating cancer is greater. Women at high risk of developing breast cancer, or diagnosed with the disease, have higher levels of estrogen-DNA adducts than women at normal risk. These results and others in humans and cell culture indicate that formation of estrogen-DNA adducts is a critical event in the initiation of cancer. Two antioxidant compounds, N-acetylcysteine and resveratrol, efficiently block formation

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“…The extremely weak carcinogen 2-OHE 1 (E 2 ) [44] also forms depurinating adducts, but to a much lesser extent [52]. The depurinating N3Ade and N7Gua adducts are released from DNA at different rates, the former instantaneously and the latter with a half-life of 3 h [52,53]. E 1 and E 2 are formed by aromatization of androstenedione and testosterone, respectively, catalyzed by cytochrome P450 (CYP) 19, aromatase ( Fig.…”

Section: Formation Metabolism and Dna Adducts Of Estrogensmentioning

confidence: 99%

“…When mouse skin [32] or rat mammary gland [33] was treated with E 2 -3,4-Q, the 4-OHE 2 -1-N3Ade and 4-OHE 2 -1-N7Gua adducts were formed. In these tissues, E 2 -3,4-Q induced mainly A to G mutations in the reporter H-ras gene, presumably because the N3Ade adducts depurinate rapidly, leading to premutagenic apurinic (AP) sites, but the N7Gua adducts depurinate relatively slowly, allowing accurate DNA repair [32,33,52,53]. These mutagenicity results suggest that E 2 -3,4-Q may be the major carcinogenic metabolite of estrogens.…”

Section: Formation Metabolism and Dna Adducts Of 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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Slow loss of deoxyribose from the N7deoxyguanosine adducts of estradiol-3,4-quinone and hexestrol-3′,4′-quinone.

Cited by 35 publications

References 12 publications

Dual roles of estrogen metabolism in mammary carcinogenesis

Dual roles of estrogen metabolism in mammary carcinogenesis

Oxidative Stress in the Metabolism of Estrogens Leading to Cancer Initiation: Prevention by Specific Antioxidants

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

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