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1.
Int J Cancer ; 87(1): 1-4, 2000 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-10861445

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) can regress adenomas in patients with familial adenomatous polyposis (FAP), and the mechanism involves inhibition of cyclooxygenases (COX). Reactive intermediates formed during the arachidonic acid cascade, notably by COX-2, which is upregulated in polyps of FAP patients, may promote various stages of the polyp --> adenoma --> carcinoma sequence. Etheno-DNA adducts can be derived from reactive intermediates generated during arachidonic acid metabolism and lipid peroxidation. We tested this hypothesis in colonic polyps from FAP patients and colorectal tissue from cancer patients to see whether increased formation of etheno-DNA adducts occurs. Using an ultra-sensitive and specific immunoaffinity/(32)P-postlabelling method, 1, N(6)-ethenodeoxyadenosine (straightepsilondA) and 3, N(4)-ethenodeoxycytidine (straightepsilondC) were quantitated in epithelial cell DNA from asymptomatic colon, FAP polyps and colon tumor tissues. Mean adduct levels in FAP polyps were 65 straightepsilondA/10(9) and 59 straightepsilondC/10(9) parent nucleotides, being 2 to 3 times higher than in unaffected colon tissue (p < 0.02 for straightepsilondA; p < 0.05 for straightepsilondC). Adduct levels in colonic epithelia decreased in the order: FAP polyps > tumor-adjacent tissue > tumor, normal and tumor-distal tissue. Based on this study, requiring confirmation in a larger number of patients and in experimental models, we have demonstrated the formation of promutagenic etheno-DNA adducts in adenomatous polyps of FAP patients that may contribute to genetic instability and cancer progression.


Assuntos
Adenoma/genética , Adenoma/metabolismo , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/metabolismo , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Adutos de DNA/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Colo/metabolismo , Desoxiadenosinas/biossíntese , Desoxicitidina/análogos & derivados , Desoxicitidina/biossíntese , Feminino , Humanos , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo
2.
Mutat Res ; 424(1-2): 59-69, 1999 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-10064850

RESUMO

Promutagenic etheno (epsilon) adducts in DNA are generated through reactions of DNA bases with LPO products derived from endogenous sources or from exposure to several xenobiotics. The availability of sensitive methods has made it possible to detect three epsilon-adducts in vivo, namely epsilon dA, epsilon dC and N2,3-epsilon dG. One probable endogenous source for the formation of these adducts arises from LPO products such as trans-4-hydroxy-2-nonenal (HNE), resulting in highly variable background epsilon-adduct levels in tissues from unexposed humans and rodents. The range of background levels of epsilon dAx10-8dA detected inhuman tissues was <0.05 to 25 and in rodent tissues 0.02 to 10; the corresponding values for epsilon dCx10-8dC were 0.01 to 11 and 0.03 to 24, respectively. Part of this variability may be associated with different dietary intake of antioxidants and/or omega-6 PUFAs which oxidize readily to form 4-hydroxyalkenals, as epsilon dA and epsilon dC levels in WBC-DNA of female volunteers on a high omega-6 PUFA diet were drastically elevated. Increased levels of etheno adducts were also found in the liver of cancer-prone patients suffering from hereditary metal storage diseases, i.e., Wilson's disease (WD) and primary hemochromatosis (PH) as well as in Long-Evans Cinnamon rats, an animal model for WD. Increased metal-induced oxidative stress and LPO-derive epsilon-adducts, along with other oxidative damage, may trigger this hereditary liver cancer. Epsilon-Adducts could hence be explored as biomarkers (i) to ascertain the role of LPO mediated DNA damage in human cancers associated with oxidative stress imposed by certain lifestyle patterns, chronic infections and inflammations, and (ii) to verify the reduction of these epsilon-adducts by cancer chemopreventive agents. This article summarizes recent results on the formation, occurrence and possible role of epsilon-DNA adducts in carcinogenesis and mutagenesis.


Assuntos
Adutos de DNA , Dano ao DNA , Peroxidação de Lipídeos , Estresse Oxidativo , Animais , Feminino , Humanos , Ratos , Espécies Reativas de Oxigênio
3.
Mutat Res ; 405(2): 125-33, 1998 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-9748537

RESUMO

DNA adducts associated with oxidative stress are believed to involve the formation of endogenous reactive species generated by oxidative damage and lipid peroxidation. Although these adducts have been reported in several human tissues by different laboratories, a comparison of the levels of these adducts in the same tissue samples has not been carried out. In this study, we isolated DNA from the pancreas of 15 smokers and 15 non-smokers, and measured the levels of 1,N6-etheno(2'-deoxy)guanosine (edA), 3, N4-etheno(2'-deoxy)cytidine (edC), 8-oxo-2'-deoxyguanosine (8-oxo-dG), and pyrimido[1,2-alpha]purin-10(3H)-one (m1G). Using the same DNA, the glutathione S-transferase (GST) M1, GSTT1, and NAD(P)H quinone reductase-1 (NQO1) genotypes were determined in order to assess the role of their gene products in modulating adduct levels through their involvement in detoxification of lipid peroxidation products and redox cycling, respectively. The highest adduct levels observed were for m1G, followed by 8-oxo-dG, edA, and edC, but there were no differences in adduct levels between smokers and non-smokers and no correlation with the age, sex or body mass index of the subject. Moreover, there was no correlation in adduct levels between edA and eC, or between edA or edC and m1G or 8-oxo-dG. However, there was a significant correlation (r=0.76; p<0.01) between the levels of 8-oxo-dG and m1G in human pancreas DNA. Neither GSTM1 nor NQO1 genotypes were associated with differences in any of the adduct levels. Although the sample set was limited, the data suggest that endogenous DNA adduct formation in human pancreas is not clearly derived from cigarette smoking or from (NQO1)-mediated redox cycling. Further, it appears that neither GSTM1 nor GSTT1 appreciably protects against endogenous adduct formation. Together with the lack of correlation between m1G and edA or edC, these data indicate that the malondialdehyde derived from lipid peroxidation may not contribute significantly to m1G adduct formation. On the other hand, the apparent correlation between m1G and 8-oxo-dG and their comparable high levels are consistent with the hypothesis that m1G is formed primarily by reaction of DNA with a base propenal, which, like 8-oxo-dG, is thought to be derived from hydroxyl radical attack on the DNA.


Assuntos
Adutos de DNA/análise , Estresse Oxidativo , Pâncreas/química , 8-Hidroxi-2'-Desoxiguanosina , Adolescente , Adulto , Criança , Citidina/análogos & derivados , Citidina/análise , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análise , Feminino , Glutationa Transferase/genética , Guanina/análogos & derivados , Humanos , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/genética , Pâncreas/enzimologia , Polimorfismo de Fragmento de Restrição , Purinas/análise , Pirimidinas/análise , Fumar
4.
Cancer Epidemiol Biomarkers Prev ; 6(8): 597-601, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9264272

RESUMO

Lipid peroxidation generates reactive aldehydes such as trans-4-hydroxy-2-nonenal and malonaldehyde, which form promutagenic exocyclic DNA adducts in human cells and may contribute to diet-related cancers. Using ultrasensitive detection methods, analysis of WBC DNA from volunteers in a dietary study revealed that high intake of omega-6 polyunsaturated fatty acids increased malonaldehyde-derived adducts in male and female subjects. In contrast, etheno adducts (1,N6-ethenodeoxyadenosine; 3,N4-ethenodeoxycytidine) were not elevated in males but were, on average, 40 times higher in females, displaying a huge intersubject variation in lipid peroxidation-derived DNA damage. Exocyclic DNA adducts are promising biomarkers for examining the hypothesis of possible links between increased intake of dietary omega-6 polyunsaturated fatty acids, DNA damage, and elevated cancer risk for breast, colon, and prostate.


Assuntos
Biomarcadores Tumorais/sangue , Adutos de DNA/sangue , Desoxiadenosinas/sangue , Desoxicitidina/análogos & derivados , Gorduras Insaturadas na Dieta/efeitos adversos , Ácidos Graxos Insaturados/efeitos adversos , Comportamento Alimentar , Neoplasias/etiologia , Adulto , Desoxicitidina/sangue , Ácidos Graxos Monoinsaturados , Ácidos Graxos Ômega-6 , Ácidos Graxos Insaturados/administração & dosagem , Feminino , Humanos , Leucócitos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Óleos de Plantas/administração & dosagem , Óleo de Brassica napus , Fatores de Risco , Fatores Sexuais , Relação Estrutura-Atividade , Óleo de Girassol
6.
Eur J Cancer Prev ; 6(6): 529-34, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9496454

RESUMO

Etheno adducts in DNA are formed from the carcinogens vinyl chloride and urethane, and also from products of lipid peroxidation (LPO), such as trans-4-hydroxy-2-nonenal. Using an ultrasensitive detection method, the formation of etheno-DNA adducts in the liver was demonstrated in LEC rats (a strain with hereditary abnormal copper metabolism) that develop hepatitis and hepatocellular carcinoma. Wilson's disease and primary haemochromatosis are human genetic disorders that cause copper or iron accumulation resulting in a high risk for primary liver cancers. Levels of etheno adducts were also significantly elevated in the liver of these patients. In a group of male and female volunteers kept on a controlled diet, the effect of dietary fatty acid composition on the endogenous formation of lipid peroxidation-derived DNA adducts was determined in DNA from white blood cells. Dietary omega-6-polyunsaturated fatty acids greatly increased LPO-derived etheno-DNA adducts in vivo, in females. Thus, exocyclic DNA adducts are promising biomarkers for elucidating the effect of dietary fat intake, oxidative stress and protective dietary antioxidants on endogenous DNA damage and thus may provide a possible mechanistic link with elevated risk for diet-related cancers.


Assuntos
Adutos de DNA/análise , Neoplasias Hepáticas/prevenção & controle , Animais , Biomarcadores , Adutos de DNA/sangue , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Feminino , Hemocromatose/genética , Degeneração Hepatolenticular/genética , Humanos , Neoplasias Hepáticas/dietoterapia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , Masculino , Malondialdeído/metabolismo , Ratos
7.
J Chromatogr B Biomed Appl ; 666(1): 139-47, 1995 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-7655612

RESUMO

A simple and accurate HPLC procedure was developed to quantify, in a single run, all phase I and phase II [14C]antipyrine metabolites that occur in rat and dog urine. All metabolites were subjected to thermospray-LC-MS and EI-MS in order to establish their structure. The rat metabolizes antipyrine to eight major metabolites, six of which are conjugated; 1.4% of the dose was excreted unchanged, 18.9% in a free form, 30.6% as sulfates and 21.1% as glucuronides. The dog metabolizes antipyrine to four metabolites, all as sulfate (61.0% of the dose) or glucuronide conjugates (16.2% of the dose).


Assuntos
Antipirina/urina , Animais , Antipirina/metabolismo , Cromatografia Líquida de Alta Pressão , Cães , Espectrometria de Massas/métodos , Ratos
8.
Cancer Res ; 54(21): 5599-601, 1994 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-7923203

RESUMO

The effect of cell replication on histone-carcinogen adducts was investigated by determining the specific adduct levels as a function of time following carcinogen treatment of human TK6 cells grown in culture. Core histones isolated from cells treated with aflatoxin B1 or r-7,t-8 dihydroxy-t-9,t-10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene exhibited a decrease over five generations in specific adduct level that did not exceed the decrease expected as a result of dilution with newly synthesized protein except during the early phase (< 1 generation) of the experiment when loss of chemically unstable adducts might occur. Similar kinetics without the initial, more rapid phase was observed when cells were treated with N-nitroso-N-methylurea. Multigeneration stability of aflatoxin B1 and N-nitroso-N-methylurea adducts that formed on histone H1 was also observed; in these experiments it was not possible to determine if there was an initial phase in the kinetics. These experiments indicate that cell replication does not result in the repair or removal of adducted histones, establishing the feasibility of using histone-carcinogen adducts for molecular dosimetry purposes.


Assuntos
Carcinógenos/metabolismo , Divisão Celular , Histonas/metabolismo , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/análise , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/metabolismo , Aflatoxina B1/análise , Aflatoxina B1/metabolismo , Carcinógenos/análise , Linhagem Celular , Histonas/análise , Humanos , Metilnitrosoureia/análise , Metilnitrosoureia/metabolismo , Fatores de Tempo
9.
IARC Sci Publ ; (127): 245-52, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8070870

RESUMO

[7-3H]Styrene 7,8-oxide was administered by oral gavage to male CD rats at a dose of 1.3 mg/kg. After 4 h, the forestomach was excised, DNA was isolated, purified to constant specific radioactivity and degraded enzymatically to the 3'-nucleotides. High-performance liquid chromatography fractions with the normal nucleotides contained most of the radiolabel, but a minute level of adduct label was also detected. Using the units of the covalent binding index (micromoles adduct per mole DNA nucleotide)/(millimole chemical administered per kilogram body weight), a DNA binding potency of 1.0 was derived. A comparison of the covalent binding indices and carcinogenic potencies of other genotoxic forestomach carcinogens showed that the tumorigenic activity of styrene oxide is unlikely to be purely genotoxic. Therefore, styrene oxide was compared with 3-t-butylhydroxyanisole (BHA) with respect to stimulation of cell proliferation in the forestomach. Male Fischer 344 rats were treated for four weeks at three dose levels of styrene oxide (0, 137, 275 and 550 mg/kg, three times per week by oral gavage) and BHA (0, 0.5, 1 and 2% in the diet); the highest doses had been reported to result in 84% and 22% carcinomas in the forestomach, respectively. Cell proliferation was assessed by incorporation of bromodeoxyuridine into DNA and immunohistochemical analysis. An increase in the labelling index was found in all treated animals. In the prefundic region of the forestomach, the labelling index increased significantly, from 42% (controls) to 54% with styrene oxide and from 41 to 55% with BHA.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Carcinógenos/toxicidade , Divisão Celular/efeitos dos fármacos , DNA/metabolismo , Compostos de Epóxi/toxicidade , Neoplasias Gástricas/induzido quimicamente , Administração Oral , Animais , Hidroxianisol Butilado/toxicidade , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Mucosa Gástrica/metabolismo , Hiperplasia , Masculino , Ligação Proteica , Ratos , Ratos Endogâmicos F344 , Estômago/citologia , Estômago/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
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