Benzo(a)pyrene Diol Epoxide-Induced Chromosome 9p21 Aberrations Are Associated with Increased Risk of Bladder Cancer

Abstract

Purpose: Loss of chromosome 9p21 is one of the most frequent genomic alterations in bladder cancer. Alterations of 9p21 and p16 are also frequently seen in the epithelial cells of chronic smokers. We hypothesize that 9p21 is a molecular target of benzo(a)pyrene diol epoxide (BPDE), the metabolic product of tobacco carcinogen benzo(a)pyrene, and 9p21 BPDE sensitivity is a genetic susceptibility factor for bladder cancer. Material and Methods: In this case-control study of 203 bladder cancer cases and 198 matched healthy controls, we compared the frequencies of BPDE-induced 9p21 aberrations in cultured peripheral blood lymphocytes using fluorescent in situ hybridization and evaluated the association between 9p21 BPDE sensitivity and bladder cancer risk. Results: We found that BPDE-induced chromosome 9p21 aberrations were significantly higher in peripheral blood lymphocytes of bladder cancer cases (20.76 F 6.97 per 1,000) than those of controls (16.58 F 7.07 per 1,000; P < 0.0001). However, no difference was observed for CEP9, a control centromere locus on chromosome 9. Using the median aberration value in the controls as a cutoff point to dichotomize BPDE sensitivity and after adjustment by age, sex, ethnicity, and smoking status, 9p21 BPDE sensitivity was associated with a significantly increased risk of bladder cancer (odds ratio, 5.29; 95% confidence interval, 3.26-8.59), whereas the odds ratio for the CEP9 locus was 0.99 (95% confidence interval, 0.66-1.50). There was also a dose-response relationship between the 9p21 BPDE sensitivity and increased risk for bladder cancer. Conclusion: 9p21 may be a molecular target for BPDE damage in bladder cancer cases and 9p21 BPDE sensitivity may be a marker of bladder cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2445 -50)

Monocrotophos Induces the Expression and Activity of Xenobiotic Metabolizing Enzymes in Pre-Sensitized Cultured Human Brain Cells

“…CYP1A1 is well known for its role in the bioactivation of carcinogens such as aromatic amines and polycyclic aromatic hydrocarbons (PAHs) [21], [22]. Induction and a high activity of the CYP1A1 have been associated with increased toxicity and cancer risk [23], [24]. CYP2B6 is also expressed in the brain, highly expressed in specific cells such as cortical pyramidal cells and astrocytes [25] and may be an important factor in the metabolism of drugs acting on the central nervous system (CNS).…”

TLR2 Controls Intestinal Carcinogen Detoxication by CYP1A1

“…Therefore, the prevalence of different Ahr alleles, which might result in the formation of proteins with different ligand affinities [41] can be excluded. (ii) Both the mRNA expression levels of both genes and the corresponding intestinal protein concentrations were unchanged in TLR2 −/− animals compared to WT mice (Table 2, Figure 2) (iii) CYP1A2, which also depends on AHR/ARNT regulation [10], is expressed at high levels in the liver and also moderately in the intestine. This would not be the case if the AHR functionality would be impaired; (iv) CYP1A1 is induced in the liver of TLR2 −/− mice after exposure to BaP, indicating a well-functioning regulation by AHR/ARNT in this organ; (v) none of the genes that were shown to be altered by genetic deletion of AHR in mice [42] were found to be significantly changed in the TLR2 −/− mice (Table 1).…”

“…Data from epidemiological studies, biochemical and molecular investigations support the idea of PAH such as BaP to be primary causative carcinogens in the lung [9] and the bladder [10]. The key reactive intermediate benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) can link covalently to DNA, therefore causing genetic aberrations [10]. BPDE is formed endogenously in a multi-step procedure in which cytochrome P450 (CYP) subclasses CYP1A1 and CYP1B1 are of special relevance in both metabolic activation (epoxidation) and detoxication [9].…”

“…Data from epidemiological studies, biochemical and molecular investigations support the idea of PAH such as BaP to be primary causative carcinogens in the lung [9] and the bladder [10]. The key reactive intermediate benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) can link covalently to DNA, therefore causing genetic aberrations [10].…”

Risk Assessment of Esophageal Adenocarcinoma Using γ-H2AX Assay

“…DNA damage/repair capacity can be quantified by phenotypic assays such as the mutagen sensitivity assay, which quantifies chromatid breaks induced by mutagens in short-term cultures of peripheral blood lymphocytes (PBLs) (8). Numerous studies have shown that individuals with higher mutagen sensitivity phenotype are at increased risk of various cancers (9–12). DNA double-strand breaks (DSBs) is one of the major forms of DNA damage.…”