Associations between smoking, GST genotypes and N7-methylguanine levels in DNA extracted from bronchial lavage cells

N7-Methylguanine (N7-MeG) DNA adducts are markers of human exposure to methylating agents including tobacco-specific nitrosamines (TSNAs). Repair of this adduct is poor, so levels in lung tissue should reflect variation in both intensity of exposure and in metabolism. N7-MeG adducts in lung DNA from bronchial lavage samples were measured to determine whether levels were higher in smokers than non-smokers, and if levels were modified by genetic variation in carcinogen-metabolising enzymes. Adducts were detected in 38 out of 44 DNA samples by (32)P post-labelling of the N7-methyldeoxyguanosine-3'-monophosphate (N7-MedGp) isolated from DNA digests by two-stage HPLC. N7-MeG adduct levels were higher in smokers than in never smokers ((9.99+/-20.3) X 10(-7) versus (0.58+/-0.50) x 10(-7) N7-MedGp/deoxyguanosine-3'-monophosphate (dGp); P = 0.02) and intermediate in ex-smokers ((5.59+/-15.6) x 10(-7) N7-MedGp/dGp). Adduct levels tended to be higher in individuals with GSTM1 null, GSTT1 null or GSTP1 ilelile genotypes. When genotypes were combined, N7-MedGp levels among GSTM1 null/GS7-T1 null individuals (n = 6) were higher than among those having at least one wild-type allele of these two genes ((26.1+/-38.0) x 10(-7) versus (2.73+/-4.07) x 10(-7) N7-MedGp/dGp), although the results were not statistically significant (P = 0.13). Adduct levels were highest in individuals with three unfavourable genotypes (GSTM1 nullIGSTT1 null and GSTP1 ilelile) compared with others ((74.5+/-13.1) X 10(-7) versus (2.64+/-3.89) X 10(-7) N7-MedGp/dGp, P = 0.02). N7-MeG adduct levels in DNA isolated from lung tissue thus reflect exposure to cigarette smoke, and genetic variation in carcinogen-metabolising enzymes may modify these levels. (C) 2004 Elsevier B.V. All rights reserved.