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

Abstract

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) and 69 of 74 subjects with GSTM1*0/*0 (93%) had 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.

Polycyclic aromatic hydrocarbon‐DNA adducts in liver tissues of hepatocellular carcinoma patients and controls

“…The effects of metabolic enzyme polymorphisms on PAH-DNA adduct levels are usually detected at high PAH exposures only, e.g., occupational exposure in coke-oven plants. 32,33 However, no effect was found among those with low-level exposure. 30 This might partly explain why no associations were found between PAH-DNA adduct levels and polymorphisms of GSTM1 and GSTP1 in our study.…”

“…31 However, the GSTM1 genotype did have an effect on adduct formation among coke-oven workers. 32,33 Combined GSTM1 and GSTP1 genetic polymorphisms also affected adduct levels in cigarette smokers. 34 However, when GSTP1 genotypes alone were compared, no statistically significant differences in adduct levels were found 34 nor were there associations between maternal white blood cell PAH-DNA adduct levels and maternal GSTP1 genotypes.…”

Role ofCYP2D6, CYP1A1, CYP2E1, GSTT1, andGSTM1 genes in the susceptibility to acute leukemias

“…mRNA expression studies showed relative expression of CYP2D6 in myeloblastic and lymphoid cell lines [5]. CYP1A1*2A variant has an increased activity, associated with a higher level of DNA adduct formation, and increased risk of carcinogenesis [48][49][50][51]. CYP1 family enzyme expressions are increased in myeloblastic and lymphoid cell lines, and CYP1 enzymes may contribute to the carcinogenesis of hematopoietic cells [5].…”

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

“…Furthermore, a positive correlation has been reported between the incidence of lung cancer and the inducibility of AHH in human lymphocytes (Gahmberg 1979;Kellerman et al 1973;Kiyohara et al 1998). Certain alleles of the human CYP1A1 gene have been implicated both in lung cancer and in prostate cancer in Japan (Hayashi et al 1992;Murata et al 1998;Rojas et al 2000), but these observations have not been reproduced in studies on Caucasian populations where the indicated alleles appear at much lower frequencies. Two closely linked mutations in particular have been studied extensively in relation to cancer risks; one results in a new restriction site (MspI) in the 3ú ntranslated region of the gene, and the other is a mutation in the 7th exon that results in an amino acid exchange (Ile to Val).…”