Carcinogenesis, Vol. 21, No. 1, 35-41,
January 2000
© 2000 Oxford University Press
Molecular Epidemiology and Cancer Prevention |
Modulation of benzo[a]pyrene diolepoxide–DNA adduct levels in human white blood cells by CYP1A1, GSTM1 and GSTT1 polymorphism
Division of Toxicology and Cancer Risk Factors and
1 Division of Biostatistics, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany,
2 Institute of Clinical Pharmacology, University Clinic Charité, Humboldt University of Berlin, Schumannstrasse 20/21, D-10098 Berlin, Germany,
3 Institut National de l'Environnement Industriel et des Risques, F-60550 Verneuil en Hallate, France and
4 Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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/108 nt) and a median of 1.6 adducts/108 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/108 nt) and 69 of 74 subjects with GSTM1*0/*0 (93%) had detectable adducts (>0.2 adducts/108 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/108 nt) compared with 26 individuals with heterozygous mutated CYP1A1*1/*2 genotypes (median 2.5, range 0.4–6.1 adducts/108 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/108 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/108 nt), but had no effect on the smokers from the exposed group (2.3 versus 2.8 adducts/108 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.
Abbreviations: B[a]P, benzo[a]pyrene; BPDE, (±)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; CYP1A1, CYTOCHROME P450 1A1 gene; CYP1A1*1/*1, wild-type; CYP1A1*1/*2 (*1/*2A, 2A/4, 2B/4), heterozygotes; CYP1A1*2/*2 (*2/*2A, 2B/ 2B), homozygotes; GSTM1, glutathione S-transferase M1 gene; GSTT1, glutathione S-transferase T1 gene; HPLC-FD, HPLC with fluorometric detection; PAH, polycyclic aromatic hydrocarbons; PAQ, number of packs of cigarettes smoked per day multiplied by the number of years of smoking.
5 To whom correspondence should be addressed Email: h.bartsch{at}dkfz-heidelberg.de.
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