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Titolo:
Host determinants of DNA alkylation and DNA repair activity in human colorectal tissue: O-6-methylguanine levels are associated with GSTT1 genotype and O-6-alkylguanine-DNA alkyltransferase activity with CYP2D6 genotype
Autore:
Povey, AC; Hall, CN; Badawi, AF; Cooper, DP; Guppy, MJ; Jackson, PE; OConnor, PJ; Margison, GP;
Indirizzi:
Paterson Inst Canc Res, Canc Res Campaign, Carcinogenesis Grp, Manchester M20 9BX, Lancs, England Paterson Inst Canc Res Manchester Lancs England M20 9BX X, Lancs, England Wythenshawe Hosp, Dept Surg, Manchester M23 9LT, Lancs, England Wythenshawe Hosp Manchester Lancs England M23 9LT M23 9LT, Lancs, England
Titolo Testata:
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
fascicolo: 1-2, volume: 495, anno: 2001,
pagine: 103 - 115
SICI:
1383-5718(20010822)495:1-2<103:HDODAA>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
METABOLIZING ENZYME EXPRESSION; INFLAMMATORY BOWEL-DISEASE; N-NITROSO COMPOUNDS; HUMAN COLON; HUMAN LUNG; GENETIC POLYMORPHISMS; LEUKOCYTE DNA; RISK-FACTORS; MALE-RATS; K-RAS;
Keywords:
DNA alkylation; O-6-methylguanine; O-6-alkylguanine-DNA alkyltransferase; GSTT; CYP2D6;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
68
Recensione:
Indirizzi per estratti:
Indirizzo: Povey, AC Univ Manchester, Sch Med, Sch Epidemiol & Hlth Sci, Oxford Rd, Manchester M13 9PT, Lancs, England Univ Manchester Oxford Rd Manchester Lancs England M13 9PT gland
Citazione:
A.C. Povey et al., "Host determinants of DNA alkylation and DNA repair activity in human colorectal tissue: O-6-methylguanine levels are associated with GSTT1 genotype and O-6-alkylguanine-DNA alkyltransferase activity with CYP2D6 genotype", MUT RES-GTE, 495(1-2), 2001, pp. 103-115

Abstract

There is increasing evidence that alkylating agent exposure may increase large bowel cancer risk and factors which either alter such exposure or its effects may modify risk. Hence, in a cross-sectional study of 78 patients with colorectal. disease, we have examined whether (i) metabolic genotypes (GSTT1, GSTM1, CYP2D6, CYP2E1) are associated with O-6-methyldeoxyguanosine (O-6-MedG) levels, O-6-alkylguanine-DNA alkyltransferase (ATase) activity or K-ras mutations, and (ii) there was an association between ATase activityand O-6-MedG levels. Patients with colon tumours and who were homozygous GSTT1*2 genotype carriers were more likely than patients who expressed GSTT1to have their DNA alkylated (83 versus 32%, P = 0.03) and to have higher O(6)0-MedG levels (0.178 +/- 0.374 versus 0.016 +/- 0.023 mu mol O-6-MedG/mol dG, P = 0.04) in normal, but not tumour, DNA. No such association was observed between the GSTT1 genotype and the frequency of DNA alkylation or O-6-MedG levels in patients with benign colon disease or rectal tumours. Patients with colon tumours or benign colon disease who were CYP2D6-poor metabolisers had higher ATase activity in normal tissue than patients who were CYP2D6 extensive metabolisers or CYP2D6 heterozygotes. Patients with the CYP2E1 Dra cd genotype were less likely to have a K-ras mutation: of 55 patientswith the wild-type CYP2E1 genotype (dd), 23 had K-ras mutations, whereas none of the 7 individuals with cd genotype had a K-ras mutation (P = 0.04). No other associations were observed between GSTT1, GSTM1, CYP2D6 and CYP2E1Pst genotypes and adduct levels, ATase activity or mutational status. O-6-MedG levels were not associated with ATase activity in either normal or tumour tissue. However, in 15 patients for whom both normal and tumour DNA contained detectable O-6-MedG levels, there was a strong positive association between the normal DNA/tumour DNA adduct ratio and the normal tissue/tumourtissue ATase ratio (r(2) = 0.66, P = 0.001). These results indicate that host factors can affect levels both of the biologically effective dose arising from methylating agent exposure and of a susceptibility factor, the DNA repair phenotype. (C) 2001 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/09/20 alle ore 12:08:08