Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones

Gaikwad, Nilesh W.; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.1016/j.freeradbiomed.2007.07.021

Cited by 68 publications

(73 citation statements)

References 32 publications

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“…One is the reduction of the quinone to the CE catalyzed by quinone reductase (Fig. 1) [47,48]. The second pathway is the reaction of the quinone with GSH.…”

Section: Resultsmentioning

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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“…One is the reduction of the quinone to the CE catalyzed by quinone reductase (Fig. 1) [47,48]. The second pathway is the reaction of the quinone with GSH.…”

Section: Resultsmentioning

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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“…Androstenedione (1), (Table I), testosterone (2), estrone (E 1 ) sulfate (3), E 2 (4), E 1 (5), 2-OHE 2 (6), 2-OHE 1 (7), 16a-OHE 2 (10), 16a-OHE 1 (11), 2-OCH 3 E 2 (12), 2-OCH 3 E 1 (13), 4-OCH 3 E 2 (14), 4-OCH 3 E 1 (15), 2-OH-3-OCH 3 E 2 (16) and 2-OH-3-OCH 3 E 1 (17) were purchased from Steraloids (Newport, RI). 4-OHE 2 (8) and 4-OHE 1 (9) were synthesized as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…There are also deactivating pathways that limit formation of the quinones and/or prevent their reaction with DNA. These are methylation of catechol estrogens, 15 conjugation of the E 1 (E 2 )-Q with glutathione (GSH) 16 and reduction of the quinones to catechols 17 ( Fig. 1).…”

mentioning

confidence: 99%

The molecular etiology of breast cancer: Evidence from biomarkers of risk

Gaikwad

Yang

Muti³

et al. 2008

Intl Journal of Cancer

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221

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Estrogens can become endogenous carcinogens via formation of catechol estrogen quinones, which react with DNA to form specific depurinating estrogen-DNA adducts. The mutations resulting from these adducts can lead to cell transformation and the initiation of breast cancer. Estrogen metabolites, conjugates and depurinating DNA adducts in urine samples from 46 healthy control women, 12 high-risk women and 17 women with breast cancer were analyzed. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry. The levels of the ratios of depurinating DNA adducts to their respective estrogen metabolites and conjugates were significantly higher in high-risk women (p < 0.001) and women with breast cancer (p < 0.001) than in control subjects. The high-risk and breast cancer groups were not significantly different (p 5 0.62). After adjusting for patient characteristics, these ratios were still significantly associated with health status. Thus, the depurinating estrogen-DNA adducts are possible biomarkers for early detection of breast cancer risk and response to preventive treatment. ' 2007 Wiley-Liss, Inc.Key words: breast cancer risk; depurinating estrogen-DNA adducts; estrogen biomarkers; balance in estrogen metabolism Development of noninvasive tests of breast cancer risk has been a major goal for more than 30 years. In this article we present biomarkers of risk that are related to the hypothesized first critical step in the initiation of breast cancer, namely, the reaction of catechol estrogen quinone metabolites with DNA.1 Prevention of cancer can be achieved by blocking this DNA damage, which generates the mutations leading to the initiation, promotion and progression of cancer. 2Exposure to estrogens is a known risk factor for breast cancer.3,4 The discovery that specific oxidative metabolites of estrogens, namely, catechol estrogen quinones, can react with DNA [5][6][7][8][9] led to and supports the hypothesis that these metabolites can become endogenous chemical carcinogens. Some of the mutations generated by this specific DNA damage can result in the initiation of cancer. 1,5 This paradigm suggests that specific, critical mutations generate abnormal cell proliferation leading to cancer. 1,[10][11][12][13] As illustrated in Figure 1, in the metabolism of catechol estrogens there are activating pathways 14 that lead to the formation of the estrogen quinones, estrone (estradiol) quinones [E 1 (E 2 )-Q], which can react with DNA. There are also deactivating pathways that limit formation of the quinones and/or prevent their reaction with DNA. These are methylation of catechol estrogens, 15 conjugation of the E 1 (E 2 )-Q with glutathione (GSH) 16 and reduction of the quinones to catechols 17 (Fig. 1). When E 1 (E 2 )-3,4-Q react with DNA, they form predominantly the depurinating adducts 4-hydroxyestrone(estradiol)-1-N3Ade-nine [4-OHE 1 (E 2 )-1-N3Ade] and 4-hydroxyestrone(estradiol)-1-N7Guanine [4-OHE 1 (E 2...

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“…Reduction is an important reaction in the metabolism and activation of quinonic drugs and xenobiotics (Testa, 1995). Alternatively, initial reduction of the quinone ring by carbonyl reductase or quinone reductase through a two-electron reduction would lead to unstable hydroxyquinone (Gaikwad et al, 2007). Oxidative cleavage of the hydroxyquinone would be expected to provide the dicarboxylic acid M2, as reported for the metabolism of pyrene (Vila et al, 2001).…”

Section: Miao Et Almentioning

confidence: 98%

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Miao¹,

Song²,

Savage³

et al. 2008

Drug Metab Dispos

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ABSTRACT:3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; ␤-lapachone) showed promising anticancer activity in phase I clinical trials as monotherapy and in combination with cytotoxic drugs. ARQ 501 is currently in multiple phase II clinical trials. In vitro incubation in fresh whole blood at 37°C revealed that ARQ 501 is stable in plasma but disappears rapidly in whole blood. Our data showed that extensive metabolism in red blood cells (RBCs) was mainly responsible for the rapid disappearance of ARQ 501 in whole blood. By comparison, covalent binding of ARQ 501 and/or its metabolites to whole blood components was a minor contributor to the disappearance of this compound. Sequestration of intact ARQ 501 in RBCs was not observed. Cross-species metabolite profiles from incubating [ 14 C]ARQ 501 in freshly drawn blood were characterized using a liquid chromatography-mass spectrometry-accurate radioactivity counter. The results show that ARQ 501 was metabolized more rapidly in mouse and rat blood than in dog, monkey, and human blood, with qualitatively similar metabolite profiles. Six metabolites were identified in human blood using ultra-high performance liquid chromatography/time-of-flight mass spectrometry, and the postulated structure of five metabolites was confirmed using synthetic standards. We conclude that the primary metabolic pathway of ARQ 501 in human blood involved oxidation of the two adjacent carbonyl groups to produce dicarboxylic and monocarboxylic metabolites, elimination of a carbonyl group to form a ring-contracted metabolite, and lactonization to produce two metabolites with a pyrone ring to form a ring-contracted metabolite. Metabolism by RBCs may play a role in clearance of ARQ 501 from the blood compartment in cancer patients.

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Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones

Cited by 68 publications

References 32 publications

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

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

The molecular etiology of breast cancer: Evidence from biomarkers of risk

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

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