Synthesis and Structure Elucidation of Estrogen Quinones Conjugated with Cysteine, <i>N</i>-Acetylcysteine, and Glutathione

Cao, Kai; Stack, Douglas E.; Ramanathan, Ragulan; Gross, Michael L.; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.1021/tx9702291

Cited by 79 publications

(78 citation statements)

References 16 publications

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“…To investigate the implications of possible COMT inhibition by Ro41-0960 and increased formation of depurinating adducts, the cells were preincubated with 3 μM Ro41-0960 and then treated with 4-OHE 2 (0.2-30 μM) for 24 h. The profile of 4-OHE 2 metabolites, conjugates and depurinating DNA adducts was determined in cell culture medium by HPLC equipped with a multichannel electrochemical detector (ECD) and validated by ultraperformance liquid chromatography (UPLC)-MS/MS techniques. This is the first report on the metabolic profile of 4-OHE 2 in MCF-10F cells treated in a dose-response manner 2 and all standards were synthesized in our laboratory, as previously described [13,[43][44][45]. Ro41-0960 and all other chemicals were purchased from Sigma (St. Louis, MO).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Zahid

Saeed

et al. 2007

Free Radical Biology and Medicine

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The association found between breast cancer development and prolonged exposure to estrogens suggests that this hormone is of etiologic importance in the causation of the disease. Studies on 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 forms depurinating adducts [4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua]. These adducts cause mutations leading to the initiation of breast cancer. Catechol-O-methyltransferase (COMT) is considered an important enzyme that protects cells from the genotoxicity and cytotoxicity of catechol estrogens, by preventing their conversion to quinones. The goal of the present study was to investigate the effect of COMT inhibition on the formation of depurinating estrogen-DNA adducts. Immortalized human breast epithelial MCF-10F cells were treated with 4-OHE 2 (0.2 or 0.5 μM) for 24 h at 120, 168, 216, and 264 h post-plating or one time at 1-30 μM 4-OHE 2 with or without the presence of COMT inhibitor (Ro41-0960). The culture media were collected at each point, extracted by solid-phase extraction and analyzed by HPLC connected with a multichannel electrochemical detector. The results demonstrate that MCF-10F cells oxidize 4-OHE 2 to E 1 (E 2 )-3,4-Q, which react with DNA to form the depurinating N3Ade and N7Gua adducts. The COMT inhibitor Ro41-0960 blocked the methoxylation of catechol estrogens, with concomitant 3-4 fold increases in the levels of the depurinating adducts. Thus, low activity of COMT leads to higher levels of depurinating estrogen-DNA adducts that can induce mutations and initiate cancer.

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Section: Introductionmentioning

confidence: 99%

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Zahid

Saeed

et al. 2007

Free Radical Biology and Medicine

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“…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. The reactions of estradiol-3,4-quinone with deoxyribo-nucleosides have been extensively studied [8, 14 -16] and the major covalent adduct formed from model reactions was detected in vivo from rats [17] or hamsters [18] treated with 4-hydroxyestradiol.…”

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confidence: 99%

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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“…One such mechanism may involve quercetin's ability to interfere with estrogen metabolism and the production of estrogen metabolites by altering the mRNA and protein levels of the key estrogen metabolizing enzymes Cyp1A1 and Cyp1B1 [5,6]. Cyp1A1 metabolizes E 2 to generate 2-OHE 2 , a relatively nongenotoxic metabolite, while Cyp1B1 metabolizes E 2 to produce 4-OHE 2 , a highly genotoxic and carcinogenic metabolite [3,5,6,11,12,15,16,[19][20][21][22]. Although quercetin increases the expression of both Cyp1A1 and Cyp1B1, it increases Cyp1A1 to a higher level compared to Cyp1B1.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, 4-OHE 2 induces DNA single strand breaks and oxidative damage [19,20]. Tumorigenic estrogen metabolites such as 4-OHE 2 undergo redox cycling to form electrophilic quinones which readily react with DNA to produce depurinating adducts [6,11,12,21]. Furthermore, redox cycling results in the formation of free radicals and reactive oxygen species [20,22].…”

Section: Introductionmentioning

confidence: 99%

Preferential induction of cytochrome P450 1A1 over cytochrome P450 1B1 in human breast epithelial cells following exposure to quercetin

Mense

Chhabra

Bhat

2008

The Journal of Steroid Biochemistry and Molecular Biology

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Estrogen metabolism is suggested to play an important role in estrogen-induced breast carcinogenesis. Epidemiologic studies suggest that diets rich in phytoestrogens are associated with a reduced risk of breast cancer. Phytoestrogens are biologically-active plant compounds that structurally mimic 17β-estradiol (E 2 ). We hypothesize that phytoestrogens, may provide protection against breast carcinogenesis by altering the expression of estrogen-metabolizing enzymes cytochrome P450 1A1 (Cyp1A1) and 1B1 (Cyp1B1). Cyp1A1 and Cyp1B1 are responsible for the metabolism of E 2 to generate 2-hydroxyestradiol (2-OHE 2 ) and 4-hydroxyestradiol (4-OHE 2 ), respectively. Studies suggest that 2-OHE 2 and 2-methoxyestradiol may protect against breast carcinogenesis, while 4-OHE 2 is carcinogenic in rodent models. Thus, agents that increase the metabolism of E 2 by Cyp1A1 to produce 2-OHE 2 may have chemoprotective properties. The human immortalized non-neoplastic breast cell line MCF10F was treated with quercetin at 10 and 50 µM concentrations for time-points ranging from 3 to 48 hours. Total RNA and protein were isolated. Real-time PCR was used to measure the expression of Cyp1A1 and Cyp1B1 mRNA. Quercetin treatment produced differential regulation of Cyp1A1 and Cyp1B1 mRNA expression in a time-and dose-dependent manner. Treatment with 10 and 50 µM doses of quercetin produced 6-and 11-times greater inductions of Cyp1A1 mRNA over Cyp1B1 mRNA, respectively. Furthermore, quercetin dramatically increased Cyp1A1 protein levels and only slightly increased Cyp1B1 protein levels in MCF10F cells. Thus, our data suggest that phytoestrogens may provide protection against breast cancer by modulating expression of estrogen-metabolizing genes such that production of the highly carcinogenic estrogen metabolite 4-OHE 2 by Cyp1B1 is reduced and the production of the less genotoxic 2-OHE 2 by Cyp1A1 is increased.

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Synthesis and Structure Elucidation of Estrogen Quinones Conjugated with Cysteine, N-Acetylcysteine, and Glutathione

Cited by 79 publications

References 16 publications

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

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

Preferential induction of cytochrome P450 1A1 over cytochrome P450 1B1 in human breast epithelial cells following exposure to quercetin

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