Role of Quinoids in Estrogen Carcinogenesis

Bolton, Judy L.; Pisha, Emily; Zhang, Fagen; Qiu, Shaofu

doi:10.1021/tx9801007

Cited by 184 publications

(225 citation statements)

References 122 publications

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“…Besides, the first unequivocal characterization of adducts involving the steroid C9 position is shown by using deuterium labeled estrogen quinones. T he enzymatic hydroxylation of the aromatic A ring of estrogens via cytochrome P450 enzymes leading to catechol estrogens represents one of the major metabolic pathways of estrogens [1][2][3]. Catechol estrogens are mainly inactivated by conversion into their O-methylated [4] or glucuronide and sulfate conjugated forms [5].…”

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confidence: 99%

“…If those preventive pathways are not completed, catechol estrogens can undergo further metabolic activation steps to quinones, highly electrophilic species that can covalently bind to nucleophilic groups, via Michael addition reactions [2, 6 -8]. In particular, the adduction of catechol estrogens to DNA bases [2,7,8] is known to induce mutations [9,10] that may initiate cancer [1,2]. The major protective pathway against this process is the reaction with glutathione [4,[11][12][13] yielding conjugates which can be easily excreted.…”

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Investigation of the regio- and stereo-selectivity of deoxyguanosine linkage to deuterated 2-hydroxyestradiol by using liquid chromatography/ESI-ion trap mass spectrometry

Debrauwer

Rathahao

Jouanin

et al. 2003

J. Am. Soc. Mass Spectrom.

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From previous studies on the reactivity of estradiol 2,3-quinone towards deoxyribonucleosides, it was demonstrated that several isomeric adducts were formed. Although adduction on steroid ring A or B has been evidenced using sequential MS n experiments, in some cases attachment positions are difficult to identify unambiguously. In this work, 2-hydroxyestradiol labeled with deuterium at various positions [6␤ (1); 6␣-7␣ (2); 6␣-6␤-7␣ (3)] have been used. Isomeric adduct differentiation could be achieved using LC-ESI-MS n . The m/z shift of the quasi-molecular ions as well as the fragmentation pathways suggested that adduction could occur on both C6 and C9 sites of the steroid B ring: Nucleophilic attack of the base on the C6 position of the steroid led to major adducts and addition of the base on the activated C9 site gave minor adducts that were found to be unstable. LC-MS n experiments carried out under deuterated medium provided information about some fragmentation processes by studying the m/z shift of fragment ions: (1) the loss of deoxyribose from the quasi-molecular ions took place according to a process involving a deuterium transfer from the deoxyribose alcohol function; (2) the cleavage of the steroid-base linkage involved a deuterium transfer from the hydroxy group of the catechol and likely occurred via the formation of an ion-dipole complex. The model studies conducted in this work provide new information on the fragmentation mechanisms of covalent adducts formed from estrogen quinones and deoxyguanosine, the most reactive DNA base. Besides, the first unequivocal characterization of adducts involving the steroid C9 position is shown by using deuterium labeled estrogen quinones. (J Am Soc Mass Spectrom 2003, 14, 364 -372)

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Investigation of the regio- and stereo-selectivity of deoxyguanosine linkage to deuterated 2-hydroxyestradiol by using liquid chromatography/ESI-ion trap mass spectrometry

Debrauwer

Rathahao

Jouanin

et al. 2003

J. Am. Soc. Mass Spectrom.

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“…8 2-Hydroxylation is a major metabolic pathway in the liver, whereas 4-hydroxylation dominates in extrahepatic organs susceptible to estrogens. 8,11,12 Catechol estrogens show much more potent carcinogenic effects on mice than estradiol. 13 Therefore, catechol estrogens can be potent carcinogens and may participate in tumor initiation by causing DNA damage.…”

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Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation

et al. 2001

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Estrogen-induced carcinogenesis involves enhanced cell proliferation (promotion) and genotoxic effects (initiation).To investigate the contribution of estrogens and their metabolites to tumor initiation, we examined DNA damage induced by estradiol and its metabolites, the catechol estrogens 2-hydroxyestradiol (2-OHE 2 ) and 4-hydroxyestradiol (4-OHE 2 ). In the presence of Cu(II), catechol estrogens formed piperidine-labile sites at thymine and cytosine residues in 32 P 5 -end-labeled DNA fragments and induced the formation of 8-oxo-7, Epidemiological studies and animal experiments have revealed that estrogens are carcinogenic. 1 In humans, elevated circulating estrogen levels, caused either by increased endogenous hormone production or by therapeutic doses of estrogen medications, increase breast and uterine cancer risk. 2 Prolonged exposure of women to high estrogen levels is associated with an elevated incidence of breast cancer. 3 Administration of estradiol to mice increased the incidence of mammary, pituitary, uterine, cervical, vaginal, testicular, lymphoid and bone tumors. 2,4 In rats, estrogen increased the incidence of mammary and/or pituitary tumors. 2,5 Estrogens can cause cancer by stimulating cell proliferation and causing genotoxic damage. 6,7 Estrogens are highly mitogenic in hormone-sensitive tissues, such as the uterus and breast. 8 Prolonged exposure of target tissues and cells to excessive mitogenic stimulation by estrogens has been considered an important etiological factor for the induction of estrogen-associated cancers in experimental animals and humans. 8 Thus, estrogens are considered to participate in tumor promotion.However, estrogens have been reported to cause cancer through their genotoxic effects. Estradiol caused sister chromatid exchanges and chromosomal aberrations in peripheral blood human lymphocyte culture, and metabolic activation enhanced these chromosomal lesions. 9 Catechol estrogens are also capable of causing chromosomal aberrations and gene mutations in cultured cells. 10 Thus, the genotoxic effects of estradiol could result from accumulation of potentially carcinogenic metabolites. Estradiol undergoes cytochrome P-450 -catalyzed hydroxylation to various catechol estrogens. 8 2-Hydroxylation is a major metabolic pathway in the liver, whereas 4-hydroxylation dominates in extrahepatic organs susceptible to estrogens. 8,11,12 Catechol estrogens show much more potent carcinogenic effects on mice than estradiol. 13 Therefore, catechol estrogens can be potent carcinogens and may participate in tumor initiation by causing DNA damage.To investigate the role of catechol estrogens in tumor initiation, we examined DNA damage induced by 2-hydroxyestradiol (2-OHE 2 ) and 4-hydroxyestradiol (4-OHE 2 ) using 32 P 5Ј-end-labeled DNA fragments obtained from the human p53 tumor-suppressor gene and the c-Ha-ras-1 proto-oncogene. We also measured the formation of 8-oxo-7,8-dihydro-2Ј-deoxyguanosine (8-oxodG), an indicator of oxidative damage to DNA, using an electrochemical detector coup...

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“…Studies in which the development of breast and endometrial cancer was associated with estrogen therapy [2][3][4][5][6] were supported by a more recent follow-up study in which it was demonstrated that post-menopausal women have an increased risk of breast cancer when using estrogens, especially in combination with progestin [7]. In animals, too, a relationship between the administration of estrogens and the development of cancer was shown [8].The carcinogenic properties of estrogens are explained by direct stimulation of cell proliferation via estrogen receptor mediated mechanisms [9,10] and by mechanisms based on metabolic activation [11][12][13][14], leading to DNA damage such as oxidative damage [15][16][17][18] and the formation of DNA-adducts [19 -28], which can cause mutations and induce cancer [29].The latter pathways are the result of metabolic activation of estrogens by the cytochrome P-450 system leading to 2-and 4-hydroxy derivatives. The 2-hydroxy estrogens are excreted in the urine as a result of their fast transformation to water-soluble compounds [13,14].…”

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confidence: 99%

“…The carcinogenic properties of estrogens are explained by direct stimulation of cell proliferation via estrogen receptor mediated mechanisms [9,10] and by mechanisms based on metabolic activation [11][12][13][14], leading to DNA damage such as oxidative damage [15][16][17][18] and the formation of DNA-adducts [19 -28], which can cause mutations and induce cancer [29].…”

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Detection of estrogen DNA-adducts in human breast tumor tissue and healthy tissue by combined nano LC-nano ES tandem mass spectrometry

Embrechts

Lemière

Dongen

et al. 2003

J. Am. Soc. Mass Spectrom.

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For the first time estrogen DNA-adducts were identified in DNA human breast tumor tissue using nano-LC coupled to nano-Electrospray Tandem Mass Spectrometry. Normal breast tissue was analyzed analogously. The data obtained in the five breast tumor and five adjacent normal tissue samples were compared qualitatively, but no straightforward difference was observed. Prior to LC-MS analysis the DNA was enzymatically hydrolyzed to a nucleoside pool. The DNA-hydrolysates were directly injected onto a column switching system developed for on-line sample clean-up and subsequent analysis of the DNA-adducts. In four patients using Premarin, DNA-adducts of 4-hydroxy-equilenin (4OHEN) were detected. All except three samples contained DNA-adducts from 4-hydroxy-estradiol or 4-hydroxy-estrone. Also DNA isolated from eight alcohol fixed and paraffin embedded breast tumor tissue showed the presence of different estrogen DNA-adducts. Worthwhile mentioning is the presence of adducts responding to m/z 570 Ͼ m/z 454 transition. This is a well-known SRM-transition indicative for the presence of the 2'-deoxyguanosine (dGuo) adduct of Benzo H ormone treatment is widespread for women of all ages. In the United States, for instance, 30% of post-menopausal women use hormone eeplacement therapy (HRT) [1], e.g., Premarin. Studies in which the development of breast and endometrial cancer was associated with estrogen therapy [2][3][4][5][6] were supported by a more recent follow-up study in which it was demonstrated that post-menopausal women have an increased risk of breast cancer when using estrogens, especially in combination with progestin [7]. In animals, too, a relationship between the administration of estrogens and the development of cancer was shown [8].The carcinogenic properties of estrogens are explained by direct stimulation of cell proliferation via estrogen receptor mediated mechanisms [9,10] and by mechanisms based on metabolic activation [11][12][13][14], leading to DNA damage such as oxidative damage [15][16][17][18] and the formation of DNA-adducts [19 -28], which can cause mutations and induce cancer [29].The latter pathways are the result of metabolic activation of estrogens by the cytochrome P-450 system leading to 2-and 4-hydroxy derivatives. The 2-hydroxy estrogens are excreted in the urine as a result of their fast transformation to water-soluble compounds [13,14]. The 4-hydroxy form, however, has a longer half-life

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Role of Quinoids in Estrogen Carcinogenesis

Cited by 184 publications

References 122 publications

Investigation of the regio- and stereo-selectivity of deoxyguanosine linkage to deuterated 2-hydroxyestradiol by using liquid chromatography/ESI-ion trap mass spectrometry

Investigation of the regio- and stereo-selectivity of deoxyguanosine linkage to deuterated 2-hydroxyestradiol by using liquid chromatography/ESI-ion trap mass spectrometry

Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation

Detection of estrogen DNA-adducts in human breast tumor tissue and healthy tissue by combined nano LC-nano ES tandem mass spectrometry

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