Modulation of DNA and protein adducts in smokers by genetic polymorphisms in GSTM1, GSTT1, NAT1 and NAT2

The formation of DNA and protein adducts by environmental pollutants is mod ulated by host polymorphisms in genes that encode metabolizing enzymes. In our study on 67 smokers, aromatic-DNA adduct levels were examined by nuclea se P1 enriched P-32-postlabelling in mononuclear blood cells (MNC) and 4-am inobiphenyl-haemoglobin adducts (4-ABPHb) by gas chromatography-mass spectr oscopy. Genetic polymorphisms in glutathione S-transferase M1 (GSTM1), T1 ( GSTT1) and N-acetyl-transferase 1 (NAT1) and 2 (NAT2) were assessed by poly merase chain reaction-based methods. DNA adduct levels, adjusted for the am ount of cigarettes smoked per day, were higher in GSTM1(-/-) individuals (1 .30 +/- 0.57 adducts per 10(8) nucleotides) than in GSTM1(+) subjects (1.03 +/- 0.56, P = 0.05), higher in NAT1 slow acetylators (1.58 +/- 0.54) than in NAT1 fast acetylators (1.11 +/- 0.58, P = 0.05) and were also found to b e associated with the NAT2 acetylator status (1.29 +/- 0.64 and 1.03 +/- 0. 46, respectively, for slow and fast acetylators, P=0.06). An effect of GSTT 1 was only found in combination with the NAT2 genotype; individuals with th e GSTT1(-/-) and NAT2-slow genotype contained higher adduct levels (1.80 +/ - 0.68) compared to GSTT1(+)/ NAT2 fast individuals (0.96 +/- 0.36), Highes t DNA adduct levels were observed in slow acetylators for both NAT1 and NAT 2 also lacking the GSTM1 gene (2.03 +/- 0.17), and lowest in GSTM1(+) subje cts with the fast acetylator genotype for both NAT1 and NAT2 (0.91 +/- 0.45 , P = 0.01). No overall effects of genotypes were observed on 4-ABP-Hb leve ls. However, in subjects smoking less than 25 cigarettes per day, 4-ABP-Hb levels were higher in NAT2 slow acetylators (0.23 +/- 0.10 ng/g Hb) compare d to fast acetylators (0.15 +/- 0.07, P=0.03). These results provide furthe r evidence for the combined effects of genetic polymorphisms in GSTM1, GSTT 1, NAT1 and NAT2: on DNA and protein adduct formation in smoking individual s and indicate that, due to the complex carcinogen exposure, simultaneous a ssessment of multiple genotypes may identify individuals at higher cancer r isk. Pharmacogenetics 11:389-398 (C) 2001 Lippincott Williams & Wilkins.