Modulation of benzo[a]pyrene diolepoxide–DNA adduct levels in human white blood cells by CYP1A1, GSTM1 and GSTT1 polymorphism

The modulation of benzo[a]pyrene diolepoxide (BPDE)-DNA adduct levels by polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes was assessed in leukocytes of Caucasian males. Eighty-nine coke oven workers (35 smokers, 36 ex-smokers and 18 non-smokers) were recruited from job categories with different exposure levels to polycyclic aromatic hydrocarbons (PAH), together with 44 power plant workers (all smokers) not exposed to PAH. BPDE-DNA adducts were detected in 69 of 133 (52%) DNA samples with a 100-fold variation (range 0.2-44 adducts/10 8 nt) and a median of 1.6 adducts/10 8 nt. All samples with the GSTM1 active genotype (n = 59) and five out of 74 samples with GSTM1 * 0/ * 0 (7%) showed non-detectable adducts ( 0.2 adducts/10 8 nt). The difference in adduct level between the GSTM1 * 0/ * 0 and GSTM1 active genotypes was highly significant (P < 0.0001). No significant difference in adduct level between the GSTT1 * 0/ * 0 and GSTT1 active genotypes was seen. All heterozygotes (CYP1A1 * 1/ * 2) from subjects of GSTM1 active type did not have detectable adducts. Among the GSTM1-deficient individuals (n = 69), 42 with the CYP1A1 * 1/ * 1 genotype showed a lower adduct level (median 1.3, range 0.2-4.1 adducts/10 8 nt) compared with 26 individuals with heterozygous mutated CYP1A1 * 1/ * 2 genotypes (median 2.5, range 0.4-6.1 adducts/10 8 nt, P < 0.015). One individual with low PAH exposure and the rare combination CYP1A1 * 2A/ * 2A-GSTM1 * 0/ * 0 showed an extremely high level of 44 adducts/10 8 nt. Significant differences in detectable adduct levels were found between the CYP1A1 * 1/ * 1 and CYP1A1 * 1/ * 2 genotypes in the exposed group low + medium (P = 0.01) and for all adduct levels, detectable and non-detectable (set at a fixed value), in highly exposed individuals and in ex-smokers (P = 0.03), whereas no such differences were observed in the control group. Mutated CYP1A1 * 1/ * 2 increased the adduct level in non-smokers from the exposed group (1.4 versus 2.2 adducts/10 8 nt), but had no effect on the smokers from the exposed group (2.3 versus 2.8 adducts/10 8 nt). When all variables were dichotomized, statistical evaluation showed that CYP1A1 status (P = 0.015), PAH exposure (P = 0.003) and smoking (P = 0.006) had significant effects on adduct levels which increased in the order: CYP1A1 * 1/ * 1 < CYP1A1( * 1/ * 2 or * 2A/ * 2A); environmental exposure < occupational exposure; non-smokers < smokers, whereby adducts increased with cigarette dose and the duration of smoking. Higher levels of BPDE-DNA adducts in individuals with the combined CYP1A1(1/ * 2 or * 2A/ * 2A)-GSTM1 * 0/ * 0 genotype suggest that these genotype combinations are at increased risk for contracting lung cancer when exposed to PAH.