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

Research output: Contribution to journalArticle

Abstract

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 32P 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)×10-7 versus (0.58±0.50) ×10-7 N7-MedGp/deoxyguanosine-3′-monophosphate (dGp); P=0.02) and intermediate in ex-smokers ((5.59±15.6)×10 -7 N7-MedGp/dGp). Adduct levels tended to be higher in individuals with GSTM1 null, GSTT1 null or GSTP1 ile/ile genotypes. When genotypes were combined, N7-MedGp levels among GSTM1 null/GSTT1 null individuals (n=6) were higher than among those having at least one wild-type allele of these two genes ((26.1±38.0)×10-7 versus (2.73±4.07) ×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 null/GSTT1 null and GSTP1 ile/ile) compared with others ((74.5±13.1)×10-7 versus (2.64±3.89)×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. © 2004 Elsevier B.V. All rights reserved.

Bibliographical metadata

Original languageEnglish
Pages (from-to)11-18
Number of pages7
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume559
Issue number1-2
DOIs
StatePublished - 11 Apr 2004