4 Hydroxyestradiol

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Ercole L Cavalieri - One of the best experts on this subject based on the ideXlab platform.

  • association of the cyp1b1 3 allele with survival in patients with prostate cancer receiving docetaxel
    Molecular Cancer Therapeutics, 2008
    Co-Authors: Tristan M Sissung, Ercole L Cavalieri, Muhammad Zahid, Romano Danesi, Douglas K Price, Seth M Steinberg, Ronald De Wit, Nilesh W Gaikwad, William L Dahut, Dan L Sackett
    Abstract:

    Using a single nucleotide polymorphism association study in 52 men with prostate cancer receiving docetaxel, we found that individuals carrying two copies of the CYP1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared with individuals carrying at least one copy of the CYP1B1*1 allele (30.6 versus 12.8 months; P = 0.0004). The association between CYP1B1*3 and response to therapy was not observed in similar subjects receiving non-taxane-based therapy ( P = 0.18). The systemic clearance of docetaxel was also unrelated to CYP1B1 genotype status ( P = 0.39), indicating that the association of CYP1B1*3 with clinical response is not due to docetaxel metabolism. To explain these results, we hypothesized that an indirect gene-drug interaction was interfering with the primary mechanism of action of docetaxel, tubulin polymerization. We therefore conducted tubulin polymerization experiments with taxanes in the presence or absence of certain CYP1B1 estrogen metabolites, which are known to bind to nucleophilic sites in proteins and DNA, that revealed the primary estrogen metabolite of CYP1B1, 4-Hydroxyestradiol (4-OHE2), when oxidized to estradiol-3,4-quinone strongly inhibits tubulin polymerization. The 4-OHE2 is also formed more readily by the protein encoded by the CYP1B1*3 allele, validating further our data in patients. Furthermore, estradiol-3,4-quinone reacted in vitro with docetaxel to form the 4-OHE2-docetaxel adduct. This pilot study provides evidence that CYP1B1*3 may be an important marker for estimating docetaxel efficacy in patients with prostate cancer. This link is likely associated with CYP1B1*3 genotype-dependent estrogen metabolism. [Mol Cancer Ther 2008;7(1):19–26]

  • mutagenic activity of 4 Hydroxyestradiol but not 2 Hydroxyestradiol in bb rat2 embryonic cells and the mutational spectrum of 4 Hydroxyestradiol
    Chemical Research in Toxicology, 2006
    Co-Authors: Zhonglin Zhao, Ercole L Cavalieri, Eleanor G. Rogan, Wieslawa Kosinska, Michael Khmelnitsky, Dhrubajyoti Chakravarti, Peter G Sacks, Joseph B Guttenplan
    Abstract:

    Estrogens are hypothesized to contribute to breast cancer via estrogen receptor-mediated increases in cell proliferation and via genotoxic processes leading to mutations. In this latter process, estradiol (E 2 ) is thought to be oxidized to 4-Hydroxyestradiol and then to E 2 -3,4-quinone, which reacts with DNA leading to apurinic sites. These sites represent premutagenic lesions. Additionally, E 2 -3,4-quinone can undergo redox cycling with E 2 -3,4-hydroquinone, leading to the release of reactive oxygen species. Although there is evidence that estradiol and E 2 -3,4-quinone are carcinogenic or mutagenic in several systems, 4-Hydroxyestradiol, a key intermediate in the proposed genotoxic pathway, has thus far been negative in mutagenesis assays. Another major metabolite of estradiol, 2-Hydroxyestradiol, is essentially inactive in carcinogenicity or mutagenicity assays. Here, we report that when using multiple low-dose exposures 4-Hydroxyestradiol is mutagenic in the cII assay in BB rat2 cells. Under similar conditions, 2-Hydroxyestradiol is inactive. Furthermore, the mutational spectrum of 4-Hydroxyestradiol contains a considerable proportion of mutations at A:T base pairs, consistent with the known ability of E 2 -3,4-quinone to form a significant fraction of DNA adducts at adenines. Thus, the results of this study support the proposal that estradiol can contribute to carcinogenesis via a genotoxic pathway.

  • the greater reactivity of estradiol 3 4 quinone vs estradiol 2 3 quinone with dna in the formation of depurinating adducts implications for tumor initiating activity
    Chemical Research in Toxicology, 2006
    Co-Authors: Muhammad Zahid, Eleanor G. Rogan, Ekta Kohli, Muhammad Saeed, Ercole L Cavalieri
    Abstract:

    Strong evidence supports the idea that specific metabolites of estrogens, mainly catechol estrogen-3,4-quinones, can react with DNA to become endogenous initiators of breast, prostate, and other human cancers. Oxidation of the catechol estrogen metabolites 4-Hydroxyestradiol (4-OHE2) and 2-OHE2 leads to the quinones, estradiol-3,4-quinone (E2-3,4-Q) and estradiol-2,3-quinone (E2-2,3-Q), respectively. The reaction of E2-3,4-Q with DNA affords predominantly the depurinating adducts 4-OHE2-1-N3Ade and 4-OHE2-1-N7Gua, whereas the reaction of E2-2,3-Q with DNA yields the newly synthesized depurinating adduct 2-OHE2-6-N3Ade. The N3Ade adducts are lost from DNA by rapid depurination, while the N7Gua adduct is lost from DNA with a half-life of ∼3 h at 37 °C. To compare the relative reactivity of E2-3,4-Q and E2-2,3-Q, the compounds were reacted individually with DNA for 0.5−20 h at 37 °C, as well as in mixtures (3:1, 1:1, 1:3, and 5:95) for 10 h at 37 °C. Depurinating and stable adducts were analyzed. In similar ...

  • metabolism and dna binding studies of 4 Hydroxyestradiol and estradiol 3 4 quinone in vitro and in female aci rat mammary gland in vivo
    Carcinogenesis, 2003
    Co-Authors: Kai Ming Li, Eleanor G. Rogan, Prabu Devanesan, Ragulan Ramanathan, Michael L Gross, Rosa Todorovic, Sheila Higginbotham, Harald Kofeler, Ercole L Cavalieri
    Abstract:

    Studies of estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation and mutagenicity have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, with DNA can generate the critical mutations initiating breast, prostate and other cancers. The endogenous estrogens estrone (E 1 ) and estradiol (E 2 ) are oxidized to catechol estrogens (CE), 2- and 4-hydroxylated estrogens, which can be further oxidized to CE quinones. To determine possible DNA adducts of E 1 (E 2 )-3,4-quinones [E 1 (E 2 )-3,4-Q], we reported previously that the reaction of E 1 (E 2 )-3,4-Q with dG produces the depurinating adduct 4-hydroxyE 1 (E 2 )-1-N7Gua [4-OHE 1 (E 2 )-1-N7Gua] by 1,4-Michael addition (Stack et al., Chem. Res. Toxicol., 1996, 9, 851). We report here that reaction of E 1 (E 2 )-3,4-Q with Ade results in the formation of 4-OHE 1 (E 2 )-1-N3Ade by 1,4-Michael addition. The N7Gua and N3Ade depurinating adducts formed both in vitro and in rat mammary gland in vivo were analyzed by HPLC with electrochemical detection and, for some samples, by LC/MS/MS. When E 2 -3,4-Q was reacted with DNA in vitro, the depurinating adducts 4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua, which are rapidly lost from DNA by cleavage of the glycosyl bond, were formed (>99% of the total adducts), as well as traces of stable adducts, which remain in DNA unless removed by repair. Similar results were obtained when 4-OHE 2 was oxidized by horseradish peroxidase, lactoperoxidase, tyrosinase or phenobarbital-induced rat liver microsomes in the presence of DNA. When 4-OHE 2 or E 2 -3,4-Q was injected into the mammary glands of female ACI rats in vivo and the mammary tissue was excised 1 h later, the depurinating adducts 4-OHE 2 -1-N3Ade and 4-OHE 2 -1-N7Gua constituted >99% of the total adducts formed. In addition, 4-OHE 2 conjugates formed by reaction of E 2 -3,4-Q with glutathione were also detected. These results demonstrate that the 4-CE are metabolized to CE-3,4-Q, which react with DNA to form primarily depurinating adducts. These adducts can generate the critical mutations that initiate cancer (Chakravarti et al., Oncogene, 2001, 20, 7945; Chakravarti et al., Proc. Am. Assoc. Cancer Res., 2003, 44, 180).

  • Spectroscopic characterization of the 4-hydroxy catechol estrogen quinones-derived GSH and N-acetylated Cys conjugates.
    Chemical research in toxicology, 2003
    Co-Authors: Ryszard Jankowiak, Ercole L Cavalieri, Yuri Markushin, Gerald J. Small
    Abstract:

    Estrogens, including the natural hormones estrone (E1) and estradiol (E2), are thought to be involved in tumor induction. Specifically, catechol estrogen quinones (CEQs) derived from the catechol estrogens 4-hydroxyestrone (4-OHE1) and 4-Hydroxyestradiol (4-OHE2) react with DNA and form DNA adducts (Cavalieri, E. L., et al. (1997) Proc. Natl Acad. Sci. U.S.A. 94, 10037). CEQs are also conjugated with GSH, a reaction that prevents damage to DNA, providing biomarkers of exposure to CEQs. Current detection limits for these analytes by HPLC with multichannel electrochemical detection are in the picomole range (Devanesan, P., et al. (2001) Carcinogenesis 22, 489). To improve the detection limit of CEQ-derived conjugates, spectrophotometric monitoring was investigated. Fluorescence and/or phosphorescence spectra of the 4-OHE1, 4-OHE2, Cys, N-acetylcysteine (NAcCys), 4-OHE1-2-SG, and 4-OHE2-2-SG conjugates and their decomposition products 4-OHE1-2-NAcCys and 4-OHE2-2-NAcCys were obtained at 300 and 77 K. It is s...

Joachim G. Liehr - One of the best experts on this subject based on the ideXlab platform.

  • Chapter 4: Estrogens as Endogenous Genotoxic Agents—DNA Adducts and Mutations
    2015
    Co-Authors: Ercole Cavalieri, Joachim G. Liehr, Krystyna Frenkel, Eleanor Rogan, Deodutta Roy
    Abstract:

    Estrogens induce tumors in laboratory animals and have been associated with breast and uterine cancers in humans. In relation to the role of estrogens in the induction of cancer, we examine formation of DNA adducts by reactive electro-philic estrogen metabolites, formation of reactive oxygen species by estrogens and the resulting indirect DNA damage by these oxidants, and, finally, genomic and gene mutations induced by estrogens. Quinone intermediates derived by oxi-dation of the catechol estrogens 4-Hydroxyestradiol or 4-hy-droxyestrone may react with purine bases of DNA to form depurinating adducts that generate highly mutagenic apu-rinic sites. In contrast, quinones of 2-hydroxylated estrogens produce less harmful, stable DNA adducts. The catechol es-trogen metabolites may also generate potentially mutagenic oxygen radicals by metabolic redox cycling or other mecha

  • 0163-769X/00/$03.00/0 Endocrine Reviews 21(1): 40–54 Copyright © 2000 by The Endocrine Society Printed in U.S.A.
    2013
    Co-Authors: Is Estradiol, Genotoxic Mutagenic Carcinogen, Joachim G. Liehr
    Abstract:

    The natural hormone 17�-estradiol (E 2) induces tumors in various organs of rats, mice, and hamsters. In humans, slightly elevated circulating estrogen levels caused either by increased endogenous hormone production or by therapeutic doses of estrogen medications increase breast or uterine cancer risk. Several epigenetic mechanisms of tumor induction by this hormone have been proposed based on its lack of mutagenic activity in bacterial and mammalian cell test systems. More recent evidence supports a dual role of estrogen in carcinogenesis as a hormone stimulating cell proliferation and as a procarcinogen inducing genetic damage. Tumors may be initiated by metabolic conversion of E 2 to 4-Hydroxyestradiol catalyzed by a specific 4-hydroxylase (CYP1B1) and by further activation of this catechol to reactive semiquinone/quinone intermediates. Several types of direct and indirect fre

  • estrogens as endogenous genotoxic agents dna adducts and mutations
    Journal of The National Cancer Institute Monographs, 2000
    Co-Authors: Ercole L Cavalieri, Eleanor G. Rogan, Joachim G. Liehr, Krystyna Frenkel, Deodutta Roy
    Abstract:

    Estrogens induce tumors in laboratory animals and have been associated with breast and uterine cancers in humans. In relation to the role of estrogens in the induction of cancer, we examine formation of DNA adducts by reactive electrophilic estrogen metabolites, formation of reactive oxygen species by estrogens and the resulting indirect DNA damage by these oxidants, and, finally, genomic and gene mutations induced by estrogens. Quinone intermediates derived by oxidation of the catechol estrogens 4-Hydroxyestradiol or 4-hydroxyestrone may react with purine bases of DNA to form depurinating adducts that generate highly mutagenic apurinic sites. In contrast, quinones of 2-hydroxylated estrogens produce less harmful, stable DNA adducts. The catechol estrogen metabolites may also generate potentially mutagenic oxygen radicals by metabolic redox cycling or other mechanisms. Several types of indirect DNA damage are caused by estrogen-induced oxidants, such as oxidized DNA bases, DNA strand breakage, and adduct formation by reactive aldehydes derived from lipid hydroperoxides. Estradiol and the synthetic estrogen diethylstilbestrol also induce numerical and structural chromosomal aberrations and several types of gene mutations in cells in culture and in vivo. In conclusion, estrogens, including the natural hormones estradiol and estrone, must be considered genotoxic carcinogens on the basis of the evidence outlined in this chapter.

  • chapter 4 estrogens as endogenous genotoxic agents dna adducts and mutations
    Journal of The National Cancer Institute Monographs, 2000
    Co-Authors: Ercole L Cavalieri, Eleanor G. Rogan, Joachim G. Liehr, Krystyna Frenkel, Deodutta Roy
    Abstract:

    Estrogens induce tumors in laboratory animals and have been associated with breast and uterine cancers in humans. In relation to the role of estrogens in the induction of cancer, we examine formation of DNA adducts by reactive electrophilic estrogen metabolites, formation of reactive oxygen species by estrogens and the resulting indirect DNA damage by these oxidants, and, finally, genomic and gene mutations induced by estrogens. Quinone intermediates derived by oxidation of the catechol estrogens 4-Hydroxyestradiol or 4-hydroxyestrone may react with purine bases of DNA to form depurinating adducts that generate highly mutagenic apurinic sites. In contrast, quinones of 2-hydroxylated estrogens produce less harmful, stable DNA adducts. The catechol estrogen metabolites may also generate potentially mutagenic oxygen radicals by metabolic redox cycling or other mechanisms. Several types of indirect DNA damage are caused by estrogen-induced oxidants, such as oxidized DNA bases, DNA strand breakage, and adduct formation by reactive aldehydes derived from lipid hydroperoxides. Estradiol and the synthetic estrogen diethylstilbestrol also induce numerical and structural chromosomal aberrations and several types of gene mutations in cells in culture and in vivo .I n conclusion, estrogens, including the natural hormones estradiol and estrone, must be considered genotoxic carcinogens on the basis of the evidence outlined in this chapter. [J Natl Cancer Inst Monogr 2000;27:75–93]

  • is estradiol a genotoxic mutagenic carcinogen
    Endocrine Reviews, 2000
    Co-Authors: Joachim G. Liehr
    Abstract:

    The natural hormone 17β-estradiol (E2) induces tumors in various organs of rats, mice, and hamsters. In humans, slightly elevated circulating estrogen levels caused either by increased endogenous hormone production or by therapeutic doses of estrogen medications increase breast or uterine cancer risk. Several epigenetic mechanisms of tumor induction by this hormone have been proposed based on its lack of mutagenic activity in bacterial and mammalian cell test systems. More recent evidence supports a dual role of estrogen in carcinogenesis as a hormone stimulating cell proliferation and as a procarcinogen inducing genetic damage. Tumors may be initiated by metabolic conversion of E2 to 4-Hydroxyestradiol catalyzed by a specific 4-hydroxylase (CYP1B1) and by further activation of this catechol to reactive semiquinone/quinone intermediates. Several types of direct and indirect free radical-mediated DNA damage are induced by E2, 4-Hydroxyestradiol, or its corresponding quinone in cell-free systems, in cells i...

Eleanor G. Rogan - One of the best experts on this subject based on the ideXlab platform.

  • mutagenic activity of 4 Hydroxyestradiol but not 2 Hydroxyestradiol in bb rat2 embryonic cells and the mutational spectrum of 4 Hydroxyestradiol
    Chemical Research in Toxicology, 2006
    Co-Authors: Zhonglin Zhao, Ercole L Cavalieri, Eleanor G. Rogan, Wieslawa Kosinska, Michael Khmelnitsky, Dhrubajyoti Chakravarti, Peter G Sacks, Joseph B Guttenplan
    Abstract:

    Estrogens are hypothesized to contribute to breast cancer via estrogen receptor-mediated increases in cell proliferation and via genotoxic processes leading to mutations. In this latter process, estradiol (E 2 ) is thought to be oxidized to 4-Hydroxyestradiol and then to E 2 -3,4-quinone, which reacts with DNA leading to apurinic sites. These sites represent premutagenic lesions. Additionally, E 2 -3,4-quinone can undergo redox cycling with E 2 -3,4-hydroquinone, leading to the release of reactive oxygen species. Although there is evidence that estradiol and E 2 -3,4-quinone are carcinogenic or mutagenic in several systems, 4-Hydroxyestradiol, a key intermediate in the proposed genotoxic pathway, has thus far been negative in mutagenesis assays. Another major metabolite of estradiol, 2-Hydroxyestradiol, is essentially inactive in carcinogenicity or mutagenicity assays. Here, we report that when using multiple low-dose exposures 4-Hydroxyestradiol is mutagenic in the cII assay in BB rat2 cells. Under similar conditions, 2-Hydroxyestradiol is inactive. Furthermore, the mutational spectrum of 4-Hydroxyestradiol contains a considerable proportion of mutations at A:T base pairs, consistent with the known ability of E 2 -3,4-quinone to form a significant fraction of DNA adducts at adenines. Thus, the results of this study support the proposal that estradiol can contribute to carcinogenesis via a genotoxic pathway.

  • the greater reactivity of estradiol 3 4 quinone vs estradiol 2 3 quinone with dna in the formation of depurinating adducts implications for tumor initiating activity
    Chemical Research in Toxicology, 2006
    Co-Authors: Muhammad Zahid, Eleanor G. Rogan, Ekta Kohli, Muhammad Saeed, Ercole L Cavalieri
    Abstract:

    Strong evidence supports the idea that specific metabolites of estrogens, mainly catechol estrogen-3,4-quinones, can react with DNA to become endogenous initiators of breast, prostate, and other human cancers. Oxidation of the catechol estrogen metabolites 4-Hydroxyestradiol (4-OHE2) and 2-OHE2 leads to the quinones, estradiol-3,4-quinone (E2-3,4-Q) and estradiol-2,3-quinone (E2-2,3-Q), respectively. The reaction of E2-3,4-Q with DNA affords predominantly the depurinating adducts 4-OHE2-1-N3Ade and 4-OHE2-1-N7Gua, whereas the reaction of E2-2,3-Q with DNA yields the newly synthesized depurinating adduct 2-OHE2-6-N3Ade. The N3Ade adducts are lost from DNA by rapid depurination, while the N7Gua adduct is lost from DNA with a half-life of ∼3 h at 37 °C. To compare the relative reactivity of E2-3,4-Q and E2-2,3-Q, the compounds were reacted individually with DNA for 0.5−20 h at 37 °C, as well as in mixtures (3:1, 1:1, 1:3, and 5:95) for 10 h at 37 °C. Depurinating and stable adducts were analyzed. In similar ...

  • metabolism and dna binding studies of 4 Hydroxyestradiol and estradiol 3 4 quinone in vitro and in female aci rat mammary gland in vivo
    Carcinogenesis, 2003
    Co-Authors: Kai Ming Li, Eleanor G. Rogan, Prabu Devanesan, Ragulan Ramanathan, Michael L Gross, Rosa Todorovic, Sheila Higginbotham, Harald Kofeler, Ercole L Cavalieri
    Abstract:

    Studies of estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation and mutagenicity have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, with DNA can generate the critical mutations initiating breast, prostate and other cancers. The endogenous estrogens estrone (E 1 ) and estradiol (E 2 ) are oxidized to catechol estrogens (CE), 2- and 4-hydroxylated estrogens, which can be further oxidized to CE quinones. To determine possible DNA adducts of E 1 (E 2 )-3,4-quinones [E 1 (E 2 )-3,4-Q], we reported previously that the reaction of E 1 (E 2 )-3,4-Q with dG produces the depurinating adduct 4-hydroxyE 1 (E 2 )-1-N7Gua [4-OHE 1 (E 2 )-1-N7Gua] by 1,4-Michael addition (Stack et al., Chem. Res. Toxicol., 1996, 9, 851). We report here that reaction of E 1 (E 2 )-3,4-Q with Ade results in the formation of 4-OHE 1 (E 2 )-1-N3Ade by 1,4-Michael addition. The N7Gua and N3Ade depurinating adducts formed both in vitro and in rat mammary gland in vivo were analyzed by HPLC with electrochemical detection and, for some samples, by LC/MS/MS. When E 2 -3,4-Q was reacted with DNA in vitro, the depurinating adducts 4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua, which are rapidly lost from DNA by cleavage of the glycosyl bond, were formed (>99% of the total adducts), as well as traces of stable adducts, which remain in DNA unless removed by repair. Similar results were obtained when 4-OHE 2 was oxidized by horseradish peroxidase, lactoperoxidase, tyrosinase or phenobarbital-induced rat liver microsomes in the presence of DNA. When 4-OHE 2 or E 2 -3,4-Q was injected into the mammary glands of female ACI rats in vivo and the mammary tissue was excised 1 h later, the depurinating adducts 4-OHE 2 -1-N3Ade and 4-OHE 2 -1-N7Gua constituted >99% of the total adducts formed. In addition, 4-OHE 2 conjugates formed by reaction of E 2 -3,4-Q with glutathione were also detected. These results demonstrate that the 4-CE are metabolized to CE-3,4-Q, which react with DNA to form primarily depurinating adducts. These adducts can generate the critical mutations that initiate cancer (Chakravarti et al., Oncogene, 2001, 20, 7945; Chakravarti et al., Proc. Am. Assoc. Cancer Res., 2003, 44, 180).

  • catechol estrogen metabolites and conjugates in different regions of the prostate of noble rats treated with 4 Hydroxyestradiol implications for estrogen induced initiation of prostate cancer
    Carcinogenesis, 2002
    Co-Authors: Ercole L Cavalieri, Prabu Devanesan, Alaa Badawi, Maarten C Bosland, Eleanor G. Rogan
    Abstract:

    Prostate carcinomas arise in 100% of Noble rats treated with estradiol and testosterone. We hypothesize that estrogens initiate prostate cancer mainly by formation of 4-catechol estrogens (CE), followed by their oxidation to catechol estrogen-3,4-quinones (CE-3,4-Q), which can react with DNA. To avoid cancer initiation, CE can be detoxified by catechol-O-methyltransferase (COMT), and CE-3,4-Q by conjugation with glutathione (GSH) or by reduction to CE, catalyzed by quinone reductase and/or cytochrome P450 reductase. To investigate the prostatic metabolism of estrogens, Noble rats were treated with the CE 4-Hydroxyestradiol (4-OHE2) or estradiol-3,4-quinone (E2-3,4-Q), and CE metabolites and conjugates were analyzed in the four regions of the prostate, which differ in susceptibility to carcinoma formation. Following treatment of rats with 4-OHE2 (6 micromol/100 g body weight in 200 microl of trioctanoin/dimethylsulfoxide (4:1) by intraperitoneal injection) for 90 min, the non-susceptible ventral (VP) and anterior (AP) prostate had higher levels of 4-methoxyCE and GSH conjugates than the susceptible dorsolateral prostate (DLP) and periurethral prostate (PUP). After treatment with the same molar amount of E2-3,4-Q, the VP and AP contained more GSH conjugates, 4-CE and 4-methoxyCE than the susceptible DLP and PUP. These results suggest that prostate areas susceptible to carcinoma induction have less protection by COMT, GSH, and quinone reductase and/or cytochrome P450 reductase, favoring reaction of CE-3,4-Q with DNA, presumably to initiate cancer.

  • catechol estrogen conjugates and dna adducts in the kidney of male syrian golden hamsters treated with 4 Hydroxyestradiol potential biomarkers for estrogen initiated cancer
    Carcinogenesis, 2001
    Co-Authors: Prabu Devanesan, Eleanor G. Rogan, Michael L Gross, Rosa Todorovic, Jiang Zhao, Ercole L Cavalieri
    Abstract:

    Formation of depurinating adducts by reaction of catechol estrogen-3,4-quinones with DNA was proposed to be a tumor initiating event by estrogens [E.L. Cavalieri et al. (1997) Proc. Natl Acad. Sci. USA, 94, 10937-10942]. Under estrogenic imbalance, oxidation of catechol estrogens to quinones may compete with their detoxification by protective enzymes. The quinones formed can be detoxified by reaction with glutathione (GSH) or can covalently bind to DNA. To provide more support for this hypothesis, we developed a method to identify and quantify GSH, cysteine (Cys) and N-acetylCys conjugates of 4-hydroxyestrogens (4-OHE) in the kidneys of male Syrian hamsters treated with 4-Hydroxyestradiol (4-OHE2) by intraperitoneal injection. The highest level of conjugates was observed 1 h after treatment, and almost none was detected after 24 h. Dose-response studies indicated conjugate formation after treatment with 0.5 micromol of 4-OHE2/100 g body weight, and formation increased up to a treatment level of 12 micromol/100 g body weight. GSH, Cys and N-acetylCys conjugates of 4-OHE were identified in the picomole range by high-performance liquid chromatography (HPLC) with multichannel electrochemical detection and confirmed by HPLC/tandem mass spectrometry. Treatment of tissue homogenates with beta-glucuronidase/sulfatase at 37 degrees C for 6 h before extraction resulted in a 12- to 20-fold increase in Cys conjugates from picomole to nanomole levels. Similar enhancement was observed by just incubating the tissue at 37 degrees C for 6 h. Evidence for the 4-OHE-1-N7Gua depurinating adducts was obtained by mass spectrometry. We conclude that GSH and Cys conjugates of the 4-OHE and the 4-OHE-N7Gua adducts can be utilized as biomarkers to detect estrogenic imbalance and potential susceptibility to tumor initiation.

Youngjoon Surh - One of the best experts on this subject based on the ideXlab platform.

  • 4 Hydroxyestradiol induces anchorage independent growth of human mammary epithelial cells via activation of iκb kinase potential role of reactive oxygen species
    Cancer Research, 2009
    Co-Authors: Sinaye Park, Eunhee Kim, Youngnam Cha, Youngjoon Surh
    Abstract:

    Estrogen is converted by cytochrome P450 1B1 to 4-Hydroxyestradiol (4-OHE(2)), a putative carcinogenic metabolite of estrogen. This catechol estrogen metabolite is oxidized further to produce a reactive quinone via semiquinone. Redox cycling between 4-OHE(2) and its quinoid generates reactive oxygen species (ROS). ROS not only causes oxidative DNA damage but also promotes neoplastic transformation of initiated cells. In the present study, 4-OHE(2) induced anchorage-independent colony formation in human mammary epithelial cells (MCF-10A). MCF-10A cells treated with 4-OHE(2) exhibited increased accumulation of intracellular ROS. The antioxidant N-acetyl-l-cysteine inhibited the neoplastic transformation induced by 4-OHE(2). ROS overproduced by 4-OHE(2) increased the nuclear translocation of nuclear factor-kappaB (NF-kappaB) and its DNA binding through induction of IkappaB kinase alpha (IKKalpha) and IKKbeta activities. The inhibition of the IKK activities with Bay 11-7082 significantly reduced the anchorage-independent growth induced by 4-OHE(2). The 4-OHE(2)-induced activation of extracellular signal-regulated kinase and Akt resulted in enhanced IKK activities and phosphorylation of IkappaBalpha, thereby inducing NF-kappaB activation and anchorage-independent growth of MCF-10A cells. In conclusion, ROS, concomitantly overproduced during redox cycling of 4-OHE(2), activates IKK signaling, which may contribute to neoplastic transformation of MCF-10A cells.

  • resveratrol inhibits tcdd induced expression of cyp1a1 and cyp1b1 and catechol estrogen mediated oxidative dna damage in cultured human mammary epithelial cells
    Carcinogenesis, 2004
    Co-Authors: Zhihua Chen, Young-jin Chun, Yeonjin Hurh, Junghwan Kim, Donghyun Kim, Kyungsun Kang, Myunghaing Cho, Youngjoon Surh
    Abstract:

    Resveratrol (3,5,4'-trihydroxystilbene), a naturally occurring phytoalexin present in grapes and other foods, has been reported to possess chemopreventive effects as revealed by its striking inhibition of diverse cellular events associated with tumor initiation, promotion and progression. In our present study, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), when treated with the cultured human mammary epithelial (MCF-10A) cells, induced the expression of cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) that are responsible for the oxidation of 17beta-estradiol to produce catechol estrogens. Resveratrol strongly inhibited the TCDD-induced aryl hydrocarbon receptor (AhR) DNA binding activity, the expression of CYP1A1 and CYP1B1 and their catalytic activities in MCF-10A cells. It also reduced the formation of 2-Hydroxyestradiol and 4-Hydroxyestradiol from 17beta-estradiol by recombinant human CYP1A1 and CYP1B1, respectively. Furthermore, resveratrol significantly attenuated the intracellular reactive oxygen species (ROS) formation and oxidative DNA damage as well as the cytotoxicity induced by the catechol estrogens. Our data suggest that CYP1A1- and CYP1B1-catalyzed catechol estrogen formation might play a key role in TCDD-induced oxidative damage, and resveratrol can act as a potential chemopreventive against dioxin-induced human mammary carcinogenesis by blocking the metabolic formation of the catechol estrogens and scavenging the ROS generated during their redox cycling.

Deodutta Roy - One of the best experts on this subject based on the ideXlab platform.

  • Chapter 4: Estrogens as Endogenous Genotoxic Agents—DNA Adducts and Mutations
    2015
    Co-Authors: Ercole Cavalieri, Joachim G. Liehr, Krystyna Frenkel, Eleanor Rogan, Deodutta Roy
    Abstract:

    Estrogens induce tumors in laboratory animals and have been associated with breast and uterine cancers in humans. In relation to the role of estrogens in the induction of cancer, we examine formation of DNA adducts by reactive electro-philic estrogen metabolites, formation of reactive oxygen species by estrogens and the resulting indirect DNA damage by these oxidants, and, finally, genomic and gene mutations induced by estrogens. Quinone intermediates derived by oxi-dation of the catechol estrogens 4-Hydroxyestradiol or 4-hy-droxyestrone may react with purine bases of DNA to form depurinating adducts that generate highly mutagenic apu-rinic sites. In contrast, quinones of 2-hydroxylated estrogens produce less harmful, stable DNA adducts. The catechol es-trogen metabolites may also generate potentially mutagenic oxygen radicals by metabolic redox cycling or other mecha

  • estrogens as endogenous genotoxic agents dna adducts and mutations
    Journal of The National Cancer Institute Monographs, 2000
    Co-Authors: Ercole L Cavalieri, Eleanor G. Rogan, Joachim G. Liehr, Krystyna Frenkel, Deodutta Roy
    Abstract:

    Estrogens induce tumors in laboratory animals and have been associated with breast and uterine cancers in humans. In relation to the role of estrogens in the induction of cancer, we examine formation of DNA adducts by reactive electrophilic estrogen metabolites, formation of reactive oxygen species by estrogens and the resulting indirect DNA damage by these oxidants, and, finally, genomic and gene mutations induced by estrogens. Quinone intermediates derived by oxidation of the catechol estrogens 4-Hydroxyestradiol or 4-hydroxyestrone may react with purine bases of DNA to form depurinating adducts that generate highly mutagenic apurinic sites. In contrast, quinones of 2-hydroxylated estrogens produce less harmful, stable DNA adducts. The catechol estrogen metabolites may also generate potentially mutagenic oxygen radicals by metabolic redox cycling or other mechanisms. Several types of indirect DNA damage are caused by estrogen-induced oxidants, such as oxidized DNA bases, DNA strand breakage, and adduct formation by reactive aldehydes derived from lipid hydroperoxides. Estradiol and the synthetic estrogen diethylstilbestrol also induce numerical and structural chromosomal aberrations and several types of gene mutations in cells in culture and in vivo. In conclusion, estrogens, including the natural hormones estradiol and estrone, must be considered genotoxic carcinogens on the basis of the evidence outlined in this chapter.

  • chapter 4 estrogens as endogenous genotoxic agents dna adducts and mutations
    Journal of The National Cancer Institute Monographs, 2000
    Co-Authors: Ercole L Cavalieri, Eleanor G. Rogan, Joachim G. Liehr, Krystyna Frenkel, Deodutta Roy
    Abstract:

    Estrogens induce tumors in laboratory animals and have been associated with breast and uterine cancers in humans. In relation to the role of estrogens in the induction of cancer, we examine formation of DNA adducts by reactive electrophilic estrogen metabolites, formation of reactive oxygen species by estrogens and the resulting indirect DNA damage by these oxidants, and, finally, genomic and gene mutations induced by estrogens. Quinone intermediates derived by oxidation of the catechol estrogens 4-Hydroxyestradiol or 4-hydroxyestrone may react with purine bases of DNA to form depurinating adducts that generate highly mutagenic apurinic sites. In contrast, quinones of 2-hydroxylated estrogens produce less harmful, stable DNA adducts. The catechol estrogen metabolites may also generate potentially mutagenic oxygen radicals by metabolic redox cycling or other mechanisms. Several types of indirect DNA damage are caused by estrogen-induced oxidants, such as oxidized DNA bases, DNA strand breakage, and adduct formation by reactive aldehydes derived from lipid hydroperoxides. Estradiol and the synthetic estrogen diethylstilbestrol also induce numerical and structural chromosomal aberrations and several types of gene mutations in cells in culture and in vivo .I n conclusion, estrogens, including the natural hormones estradiol and estrone, must be considered genotoxic carcinogens on the basis of the evidence outlined in this chapter. [J Natl Cancer Inst Monogr 2000;27:75–93]