title: CYP1A1 and GSTM1 genotypes affect benzo[a]pyrene DNA adducts in smokers' lung: comparison with aromatic/hydrophobic adduct formation.
abstract: Benzo[a]pyrene diol epoxide (BPDE)-DNA adducts are involved in the induction of p53 mutations and probably in the causation of human lung cancer associated with cigarette smoking. The ratio between CYP1A1 and GST enzyme activities is a critical determinant of the target dose of carcinogenic BPDE and other DNA-reactive PAH metabolites. In this review, we summarize the published data on modulation of (+)-anti-BPDE-DNA adduct levels in smokers' lungs by CYP1A1*2 genotypes alone or in combination with GSTM1 polymorphism and compare these results with those reported for aromatic/hydrophobic (bulky) DNA adducts. The data published so far show only a trend for a non-significant increase in bulky DNA adduct levels in subjects with GSTM1*0 or the CYP1A1*2-GSTM1*0 genotype combination. In contrast, a clear dependence of (+)-anti-BPDE-DNA adduct levels was found as a function of the CYP1A1 and GSTM1 genotypes: In lung parenchyma, this adduct was more pronounced in persons with the GSTM1*0 genotype, and CYP1A1*2-GSTM1*0 carriers had higher (+)-anti-BPDE-DNA adduct levels than those with CYP1A1*1/*1-GSTM1*0. The homozygous CYP1A1*2/*2 carriers in the GSTM1*0 group had the highest (+)-anti-BPDE-DNA adduct levels. Our analysis leads to the conclusion that the risk-modifying effects of metabolic genotypes and of gene interactions might be more easily identifiable if specific markers of structurally defined adducts were used, such as the (+)-anti-BPDE-DNA adduct. These results are also consistent with the hypothesis that BP (PAH) induce G:C to T:A transversion mutations in the hotspot codons of the p53 tumor suppressor gene and are thus involved in malignant transformation of the lung tissue of smokers.
authors.affiliation: German Cancer Research Center (DKFZ), Division of Toxicology and Cancer Risk Factors, P.O. Box 101949, D-69009 Heidelberg, Germany.
authors.forename: Kroum
authors.initials: K
authors.lastname: Alexandrov
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.forename: Margarita
authors.initials: M
authors.lastname: Rojas
authors.forename: Guy
authors.initials: G
authors.lastname: Bouvier
authors.forename: Erik
authors.initials: E
authors.lastname: Kriek
authors.forename: Helmut
authors.initials: H
authors.lastname: Bartsch
mesh_terms: D001564:Benzo(a)pyrene / Q000378:metabolism*; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D018736:DNA Adducts / Q000378:metabolism*; D005260:Female; D016158:Genes, p53; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D009154:Mutation; D012907:Smoking
chemical_list: D001564:Benzo(a)pyrene; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D018736:DNA Adducts; D005982:Glutathione Transferase