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Titolo:
Ethanol enhances the formation of endogenously and exogenously derived adducts in rat hepatic DNA
Autore:
Navasumrit, P; Ward, TH; OConnor, PJ; Nair, J; Frank, N; Bartsch, H;
Indirizzi:
Christie NHS Trust, Canc Res Campaign, Carcinogenesis Grp, Manchester M20 4BX, Lancs, England Christie NHS Trust Manchester Lancs England M20 4BX 0 4BX, Lancs, England Christie NHS Trust, Paterson Inst Canc Res, Manchester M20 4BX, Lancs, England Christie NHS Trust Manchester Lancs England M20 4BX 0 4BX, Lancs, England Deutsch Krebsforschungszentrum, Div Toxicol & Canc Risk Factors, D-69120 Heidelberg, Germany Deutsch Krebsforschungszentrum Heidelberg Germany D-69120 lberg, Germany
Titolo Testata:
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
fascicolo: 1-2, volume: 479, anno: 2001,
pagine: 81 - 94
SICI:
1386-1964(20010808)479:1-2<81:EETFOE>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
FREE-RADICAL GENERATION; LIPID-PEROXIDATION; INDUCIBLE CYTOCHROME-P450; N-NITROSODIMETHYLAMINE; OXIDATIVE STRESS; COMET ASSAY; LIVER DNA; ALCOHOL; REPAIR; O-6-METHYLGUANINE;
Keywords:
ethanol; lipid peroxidation; CYP 2E1; etheno-DNA adducts; O-6-methylguanine; N-nitrosodimethylamine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
59
Recensione:
Indirizzi per estratti:
Indirizzo: O'Connor, PJ Christie NHS Trust, Canc Res Campaign, Carcinogenesis Grp, Manchester M20 4BX, Lancs, England Christie NHS Trust Manchester Lancs England M20 4BX England
Citazione:
P. Navasumrit et al., "Ethanol enhances the formation of endogenously and exogenously derived adducts in rat hepatic DNA", MUT RES-F M, 479(1-2), 2001, pp. 81-94

Abstract

To investigate the role of ethanol in chemical-ly-induced carcinogenesis, we exposed Wistar rats to ethanol, either as an acute dose or for prolongedperiods in a liquid diet and looked for effects on endogenously and exogenously derived DNA adducts. Changes in the cytochrome P450 protein (CYP 2E1)and its catalytic demethylase activity were also followed in order to provide a sequence of relatively well understood changes that are associated with free radical production and, therefore, potentially capable of affectingDNA. The exocyclic DNA adducts, ethenodeoxyadenosine (epsilon dA) and ethenodeoxycytidine (epsilon dC), known to arise from oxidative stress and lipid peroxidation (LPO) sources, were detected in the liver DNA of Wistar rats at background concentrations of 4-6 (epsilon dA) and 25-35 (epsilon dC) adductsper 10(9) parent bases. When rats were given either an acute dose of ethanol (5 g/kg, i.g.) or exposed for I week to ethanol in a liquid diet (5%, w/v), etheno adduct levels were increased similar to2-fold and this was statistically significant for epsilon dC (P < 0.05 and P < 0.02, respectively) for the two separate treatments. In N-nitrosodimethylamine (NDMA)-treated rats, acute ethanol treatment significantly increased the level of O-6-methylguanine (O-6-MeG) in hepatic DNA and this was paralleled by a decrease in O-6-alkylguanine DNA alkyltransferase (ATase) activity; immunohistochemistry confirmed this increase of O-6-MeG in both hepatic and renal nuclei. When rats were given ethanol in the diet and treated with NDMA, O-6-MeG levels in hepatic DNA increased at I week which coincided with the peak of CYP 2E1-dependent NDMA-demethylase activity. Single cell gel electrophoresis of liver cells showed that after I week of exposure to ethanol, there was a small but significant increase in the frequency of DNA strand breaks induced by NDMA (P < 0.05); after 4 weeks the increase was 1.4-fold (P < 0.01). Our results indicate that exposures to ethanol, which resulted in blood ethanol concentrations similar to those seen in chronic alcoholics and increased levels of expression of the CYP 2E1 protein can exacerbate the DNA damaging effects of endogenous and exogenous alkylating agents. These observations provide indications of possible mechanisms for the carcinogenic or co-carcinogenic action of ethanol. (C) 2001 Elsevier Science B.V. All rights reserved.

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Documento generato il 01/04/20 alle ore 18:47:29