The Role of Glutathione and Glutathione S‐Transferases in Mercapturic Acid Biosynthesis

Boyland, E.; Chasseaud, L. F.

doi:10.1002/9780470122778.ch5

Cited by 332 publications

(99 citation statements)

References 217 publications

(146 reference statements)

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“…Small, but increasing amounts of the GSH and Cys conjugates were detected after successive treatments with 4-OHE 2 . The 4-OHE 1 (E 2 )-2-Cys conjugates are presumably obtained by mercapturic acid biosynthesis from the 4-OHE 1 (E 2 )-2-SG [46] and by conjugation of E 1 (E 2 )-3,4-Q with the 0.4 mM Cys present in the culture medium. The presence of Cys in the medium diminishes the significance of these results.…”

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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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 GSH conjugates of estrogen quinones are further converted to Cys and NAcCys conjugates via the mercapturic acid biosynthesis pathway. 29 Hence we have combined all the values of 2 conjugates and 4 conjugates (Tables II and III), which reflect the total protection by GSH from 2 or 4 quinones, respectively. The results presented here clearly demonstrate the ability of SPE combined with UPLC/MS-MS analysis to resolve, identify and quantify 40 estrogen-related compounds with accuracy and speed.…”

Section: Analysis Of Urine Samplesmentioning

confidence: 99%

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

Gaikwad

Yang

Muti³

et al. 2008

Intl Journal of Cancer

117

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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“…67 Dependendo das características da porção derivada do xenobiótico (X), o correspondente ácido mercaptúrico poderá ser diretamente excretado na urina, ou passar por metabolização para ser eliminado. 68 É importante observar que as enzimas GSTs fazem parte de um sistema de defesa integrado, e que a eficiência deste sistema depende da ação combinada de outras enzimas, como a γ-glutamilcisteína sintase (γGluCysS) e a glutationa sintase, no sentido de fornecer glutationa, bem como de transportadores que facilitem a eliminação dos conjugados de GSH.…”

Section: Metabolismo De Xenobióticos: Detoxificação Ou Bioativação?unclassified

Glutationa e enzimas relacionadas: papel biológico e importância em processos patológicos

Huber¹,

Almeida²,

Fátima³

2008

Quím. Nova

121

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Recebido em 22/2/07; aceito em 6/9/07; publicado na web em 9/4/08 GLUTATHIONE AND RELATED ENZYMES: BIOLOGICAL ROLES AND IMPORTANCE IN PATHOLOGICAL PROCESSES. Glutathione (GSH) and related enzymes are pivotal for the normal functioning of several important biological processes. In this review we discuss the biosynthesis and the catalytic cycles of glutathione as well as the major GSH-related enzymes. We also present how glutathione and enzymes are involved in cancer and the chromatographic and non-chromatographic methods used to analyze glutathione and/or its derivatives.Keywords: glutathione; oxidative stress; cancer. INTRODUÇÃOA glutationa (GSH, 1, Figura 1), possui papel central na biotransformação e eliminação de xenobióticos e na defesa das cé-lulas contra o estresse oxidativo.1 Este tripeptídeo é encontrado intracelularmente em altas concentrações, essencialmente em todos os organismos aeróbicos. Nota-se a ligação γ-peptídica pouco usual, a presença da porção γ-glutamil e do grupo α-carboxilato livre prevenindo a hidrólise da GSH pelas peptidases celulares que degradam outros peptídeos pequenos. A GSH é o mais abundante tiol celular de baixa massa molecular; a sua concentração é ~ 2mM e mais de 10 mM em eritrócitos humanos e hepatócitos, respectivamente.1 Face à potencialidade de inibidores das enzimas relacionadas à GSH como alvo para o desenvolvimento de substâncias candidatas a fármacos, nesta revisão serão apresentados aspectos importantes do papel fisiológico da glutationa (GSH) e sua implicação em patologias. Considerando esta abordagem, ênfase especial será dada às glutationas transferase e redutase. Uma vez que a investigação do envolvimento da GSH em processos fisiopatológicos requer sua detecção e quantificação em diferentes matrizes, também serão abordados os principais métodos de análise deste tripeptídeo e derivados.Muitas das reações da GSH envolvem o grupo sulfidrila (SH), altamente polarizável, tornando-o um bom nucleófilo para reações com compostos químicos eletrofílicos. Esta habilidade de doar elé-trons a outros compostos também faz da glutationa um bom redutor. A combinação de sua abundância nos organismos aeróbicos e das propriedades químicas do grupo sulfidrila suporta a proposta de que a GSH surgiu na evolução bioquímica como uma proteção contra espécies reativas de oxigênio e compostos eletrofílicos gerados por processos oxidativos, tanto no organismo quanto no ambiente em que este vive. BiossínteseA biossíntese da GSH ocorre no meio intracelular (exceto em células epiteliais), pela ação consecutiva de duas enzimas. Na primeira reação, é formada uma ligação peptídica entre os aminoácidos glutâmico (2, Figura 2) e cisteína (3), catalisada pela enzima γ-glutamilcisteína sintetase, levando à γ-L-glutamil-L-cisteína (4). Este dipeptídeo é então ligado à glicina pela ação da glutationa sintetase. Estas etapas requerem ATP e Mg +2 . A γ-glutamilcisteína sintetase sofre regulação pela GSH através de um feedback negativo, o que previne a produção excessiva desta ou o acúmulo do intermediário...

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The Role of Glutathione and Glutathione S‐Transferases in Mercapturic Acid Biosynthesis

Cited by 332 publications

References 217 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

Glutationa e enzimas relacionadas: papel biológico e importância em processos patológicos

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