Journal Article

<i>CYP1A1</i> and <i>GSTM1</i> genotypes affect benzo[<i>a</i>]pyrene DNA adducts in smokers' lung: comparison with aromatic/hydrophobic adduct formation

Kroum Alexandrov, Ingolf Cascorbi, Margarita Rojas, Guy Bouvier, Erik Kriek and Helmut Bartsch

in Carcinogenesis

Volume 23, issue 12, pages 1969-1977
Published in print December 2002 | ISSN: 0143-3334
Published online December 2002 | e-ISSN: 1460-2180 | DOI:
CYP1A1 and GSTM1 genotypes affect benzo[a]pyrene DNA adducts in smokers' lung: comparison with aromatic/hydrophobic adduct formation

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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.

Keywords: BP, benzo[a]pyrene; BPDE, benzo[a]pyrene-diolepoxide; BPDE-DNA adduct, (+)-anti-benzo[a]pyrene-diol epoxide-DNA adduct; CYP, cytochrome P450; GST, glutathione S-transferase; HPLC-FD, high-performance liquid chromatography with fluorescence detection; NAT, N-acetyltransferase; PAH, polycyclic aromatic hydrocarbons; nt, nucleotide

Journal Article.  6940 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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