High benzo[a]pyrene diol-epoxide DNA adduct levels in lung and blood cells from individuals with combined CYP1A1 MspI/Msp-GSTM1*0/*0 genotypes.

Levels of anti-benzo[a]pyrene diol-epoxide DNA adducts were analysed by high-pressure liquid chromatography/fluorimetric detection in non-tumorous lung tissues from 20 lung cancer patients and in white blood cells from 20 polycyclic aromatic hydrocarbon exposed coke oven workers. All were current tobacco smokers. CYP1A1 mutations (MspI at 6235 nt, Ile-Val462) and GSTM1 deletion polymorphisms in each individual were analysed in genomic DNA by PCR/restriction fragment length polymorphism. Independently of the CYP1A1 genotype (1) all 23 samples in the two groups with non-detectable adducts (< 0.2 per 10(8) nt) were of GSTM1 active genotype; (2) the 17 samples with detectable adducts (> or = 0.2 per 10(8) nt) in the two groups were GSTM1*0/*0. The difference in adduct levels between GSTM1*0/*0 and GSTM1 active genotype was highly significant (p < 0.00005). Among GSTM1-deficient individuals (n = 17), a subgroup of 14 individuals with CYP1A1*1/*1 (wild-type, n = 7) or heterozygous genotype (*1/*2A or *1/*2B, n = 7) showed low levels of BPDE DNA-adducts (range: 0.2-1.3 per 10(8) nt). (3) Three individuals with the rare combination CYP1A1*2A/*2A or *2A/*B and GSTM1*0/*0 showed significantly higher adduct levels (median: 17.4 adducts/10(8) nt, range 1.9-44; p = 0.017). Therefore, combination of homozygous mutated CYP1A1 and GSTM1*0/*0 genotypes lead, at a similar or even lower smoking dose, to a stronger increase of anti-benzo[a]pyrene diol-epoxide DNA adduct levels than found in individuals with CYP1A1 and GSTM1 wild-type. These data provide a mechanistic understanding of epidemiological studies that correlated these 'at risk' genotypes with increased smoking-related lung cancers.