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

There is increasing evidence that alkylating agent exposure may increase la rge bowel cancer risk and factors which either alter such exposure or its e ffects may modify risk. Hence, in a cross-sectional study of 78 patients wi th colorectal. disease, we have examined whether (i) metabolic genotypes (G STT1, 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 activity and O-6-MedG levels. Patients with colon tumours and who were homozygous GS TT1*2 genotype carriers were more likely than patients who expressed GSTT1 to 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 obse rved between the GSTT1 genotype and the frequency of DNA alkylation or O-6- MedG levels in patients with benign colon disease or rectal tumours. Patien ts with colon tumours or benign colon disease who were CYP2D6-poor metaboli sers had higher ATase activity in normal tissue than patients who were CYP2 D6 extensive metabolisers or CYP2D6 heterozygotes. Patients with the CYP2E1 Dra cd genotype were less likely to have a K-ras mutation: of 55 patients with the wild-type CYP2E1 genotype (dd), 23 had K-ras mutations, whereas no ne of the 7 individuals with cd genotype had a K-ras mutation (P = 0.04). N o other associations were observed between GSTT1, GSTM1, CYP2D6 and CYP2E1 Pst genotypes and adduct levels, ATase activity or mutational status. O-6-M edG levels were not associated with ATase activity in either normal or tumo ur tissue. However, in 15 patients for whom both normal and tumour DNA cont ained detectable O-6-MedG levels, there was a strong positive association b etween the normal DNA/tumour DNA adduct ratio and the normal tissue/tumour tissue ATase ratio (r(2) = 0.66, P = 0.001). These results indicate that ho st factors can affect levels both of the biologically effective dose arisin g from methylating agent exposure and of a susceptibility factor, the DNA r epair phenotype. (C) 2001 Elsevier Science B.V. All rights reserved.