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.

Associations between Smoking, Polymorphisms in Polycyclic Aromatic Hydrocarbon (PAH) Metabolism and Conjugation Genes and PAH-DNA Adducts in Prostate Tumors Differ by Race

“…Because immunoassay methods are more specific to PAH [BPDE and other similar structured]-DNA adducts whereas 32 P-postlabeling methods measure all hydrophobic DNA adducts (68) and results differ considerably between these two methods (69), we restrict our comparison to those studies using immunoassay methods similar to the one we used. In lung tumor tissue, the variant alleles of the CYP1A1 1*/2* (includes CYP1A1 Ile 462 Val) and the GSTM1 null deletion polymorphisms have been positively associated with (+)anti -BPDE -DNA adduct levels, and the effect was more pronounced in individuals with both polymorphisms (48). In addition, carrying the GSTM1 null deletion has been shown to be positively associated with PAH-DNA adducts in tumor and adjacent nontumor cells obtained from breast cancer cases (49), but this effect was not found in another study (50).…”

“…Although associations between a few of the aforementioned polymorphisms in metabolism and conjugation genes and PAH-DNA adduct levels have been examined in human lung (48) and breast (49,50) cancer tissues and differences in PAH-DNA adduct levels by race in mononuclear cells have been reported (51), no prior studies have evaluated effects of these polymorphisms on adduct levels in human prostate cancer tissues. Therefore, in this study, we extend our earlier work …”

Cigarette Smoking and Risk of Non-Hodgkin's Lymphoma—A Population-Based Case-Control Study

“…For cigarette smoking, polymorphisms in the glutathione S-transferase (GST) gene, which encodes for polycyclic aromatic hydrocarbons involved in the metabolism of tobacco carcinogens, have been shown to affect the risk of lung cancer (48,49). A potential etiologic role of the polymorphism has also been suggested for non-Hodgkin's lymphoma in some studies (50)(51)(52)(53).…”

CYP1A2*1F and GSTM1 Alleles Are Associated with Susceptibility to Porphyria Cutanea Tarda

“…This promoter variant was associated with PCT in two European studies, but not in a third (17)(18)(19). Variants in CYP1A1 have been associated with differences in metabolism of polycyclic aromatic hydrocarbons and steroid hormones (20)(21)(22)(23)(24). The CYP1A1*4 gene variant was associated with PCT in one study, but only with type 2 disease (25).…”