Sex differences in risk of lung cancer: Expression of genes in the PAH bioactivation pathway in relation to smoking and bulky DNA adducts

Abstract

It is controversial whether women have a higher lung cancer susceptibility compared to men. We previously reported higher levels of smoking-related bulky DNA adducts in female lungs. In a pilot study (27 cases), we also found a higher level of female lung cytochrome P4501A1 (CYP1A1) gene expression. In the present extended study we report on the pulmonary expression of several genes involved in polycyclic aromatic hydrocarbon bioactivation in relation to sex, smoking and DNA adducts. CYP1A1, CYP1B1, aryl hydrocarbon receptor and microsomal epoxide hydrolase gene expression was measured by quantitative real-time reverse transcriptase-PCR in 121 normal lung tissue samples. The expression of CYP1A1 and CYP1B1 was significantly higher among current smokers compared to ex-smokers and never-smokers. Among current smokers, females had a 3.9-fold higher median level of CYP1A1 compared to males (p 5 0.011). CYP1B1 expression was not related to sex. Lung DNA adducts (measured by 32 P-postlabeling) were highly significantly related to CYP1A1 (p < 0.0001) irrespective of smoking-status. Our results are consistent with the hypothesis that CYP1A1 plays a significant role in lung DNA adduct formation and support a higher susceptibility to lung cancer among females. ' 2006 Wiley-Liss, Inc.Key words: lung cancer; sex differences; cytochrome P450; DNA adducts Lung cancer ranks first among cancer deaths in the world and tobacco smoke is the major causative agent.1 Although controversial, one of the puzzles in lung carcinogenesis is that women may be at higher risk of smoking associated lung cancer than men. 2-4Two significant, recent epidemiological studies have come to different conclusions. Using base-line CT screening for lung cancer and contrasting women with men, a prevalence-odds ratio of 2.7 was found.5 These data were combined from 2 independent substudies both leading to the same conclusion. From the analysis of data from the Nurses' Health Study of women and the Health Professionals Follow-up Study of men, however, the female to male hazard ratio was only 1.11 (95% CI 0.95-1.31).6 Thus, the question about females as more susceptible to lung cancer remains challenged.Polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene (B[a]P) are present in tobacco smoke, urban air and the working environment, and the B[a]P diol-epoxide metabolite (BPDE) has been established as a lung cancer etiologic agent. There is a strong coincidence of G:C to T:A transversion hotspots in lung cancers at sites of preferential formation of BPDE adducts along the TP53 gene in vitro. 7,8 In the IARC TP53 database, lung G:C to T:A transversions were found to have a higher frequency among female smokers compared to female never-smoker. In contrast, there were no major differences in the mutational spectra of male never-smokers and smokers.9 This may indicate a specific role of tobacco smoke carcinogens (PAH) in generating this particular signature mutation in women.After diffusing into the cell, PAH bind to the aryl hydrocarbon receptor (AHR). Li...

DNA methylation of the CYP1A1 enhancer is associated with smoking‐induced genetic alterations in human lung

“…6,15 We are showing here that DNA methylation of CYP1A1 enhancer inversely correlate with (i) the mRNA levels of CYP1A1 and (ii) levels of smoking-induced DNA adducts in histologically normal human lung tissues. Thus, in addition to the important role played by smoking-induced activation of the AHR/ARNT complex, inter-individual differences in CYP1A1 mRNA levels and in smoking-induced DNA damage may be due to inter-individual differences in DNA methylation of CYP1A1 enhancer.…”

“…15,37 Although methylation of the CYP1A1 enhancer region B was significantly higher in lung adenocarcinoma cell lines of male origin compared to female cell lines (data not shown), DNA methylation did not appear to be involved in sex differences in CYP1A1 gene expression in vivo. It should be noted that CYP1A1 gene expression can also be regulated by modifications of histone marks, and variations in AHR co-activators expression or activity.…”

“…13 Thus, CYP1A1 gene expression and activity might be relevant factors for formation of major genetic alterations in lung cancer. 6,7,14,15 In addition to genomic base pair differences, gene expression can be altered by epigenetic changes such as DNA methylation and covalent modifications of histones. 16 The enhancer of CYP1A1 gene contains a transcriptional control region located several hundred base pairs upstream of the transcription start site.…”

Combinations of cytochrome P-450 genotypes and risk of early-onset lung cancer in Caucasians and African Americans: A population-based study

“…It should be noted that these findings were based on 109 cases and 423 controls, of which only 9 individuals carried the C/C genotype. While an early functional study suggested that CYP1A1 MspI variant genotypes result in increased ethoxyresorufin-O-deethylase (EROD) activity [21], later studies suggest that differing expression levels are due to polymorphisms in CYP1A1 exon 7 Ile 462 Val [22,23], and may also be influenced by smoking status [24] and gender [25,26].…”

Oxidative stress, plasma/salivary antioxidant status detection and health risk factors

“…8 A link between cardiovascular disease and lung cancer in women, through oxidative stress has been supposed by a study run on a large cohort of patients with previous atherosclerotic disease-the female patients are more sensitive to tobacco-induced carcinogenesis than men, since a higher level of lung cytochrome P4501A1 (CYP1A1) gene expression in women plays a significant role in lung DNA adduct formation and supports a higher susceptibility to lung cancer among women. 35 Furthermore, we can suppose that the gender-different antioxidant status added to the less frequent women daily physical exercise, and/or the combination with other risk factors including ageing, smoking habit, obesity might share a co-aetiologic role in the diseases, such as cardiovascular diseases.…”