Elsevier

Toxicology Letters

Volume 198, Issue 1, 15 September 2010, Pages 63-68
Toxicology Letters

Mini-review
The critical DNA damage by benzo(a)pyrene in lung tissues of smokers and approaches to preventing its formation

https://doi.org/10.1016/j.toxlet.2010.04.009Get rights and content

Abstract

Benzo(a)pyrene (BP) and cadmium are environmental pollutants found in foodstuffs, cigarette smoke, and polluted air. BP is converted in liver and lung to benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) by the enzymes of the cytochrome P450 (CYP) superfamily, namely CYP1A1/1A2, and CYP1B1. BPDE reacts with DNA primarily at the N2-position of guanine, producing benzo(a)pyrene-7,8-diol-9,10-epoxide-N2-deoxyguanosine (BPDE-dG) adduct. BPDE reacts with DNA also at N6 position of adenine, producing the minor N6-deoxyadenosine adduct, but BPDE-dG adduct is a well-established risk factor for lung cancer. We thus argue that BPDE-dG adduct could be used as a model biomarker in searching and validating of approaches to reducing lung cancer risk. If the formation of BPDE-dG adduct were to be inhibited or blocked in bronchial epithelial cells, so could lung cancer development. The best way to lower BPDE-dG formation in the lung is to stop smoking. However, the following approaches could also be considered for highly addicted smokers: (a) decrease BP and cadmium intake from food, cigarettes and other environmental sources; (b) avoid meat and other food high in BP and cadmium; (c) decrease the CYP-mediated conversion of BP in liver and lung; (d) lower free radicals and cadmium in cigarette smoke; and (e) increase BPDE detoxification.

Introduction

The development of cancer in the lungs of chronic cigarette smokers is thought to be caused by the carcinogens present in tobacco products. More than 60 carcinogens have been found in cigarettes. Identification of relevant carcinogens and their carcinogenic mechanisms are warranted to develop approaches to lung cancer prevention. Benzo(a)pyrene (BP) was the first detected carcinogen in cigarette smoke and it has become one of the most extensively studied cancer-causing agents in the past century (Osborn and Crosby, 1987). BP is found also in foodstuffs, automobile emission exhaust and industrial waste (Waldman et al., 1991). Although it is difficult to have direct proof of BP being a primary causative agent in human lung cancer, the available data from carcinogenicity studies, biochemical and molecular biological investigations support a significant role for BP in tobacco-induced lung cancer in those who chronically smoke cigarettes. Cadmium is another carcinogen detected in cigarette smoke and foodstuffs because of its persistence in the environment and high-rates of the food chain transfer (Satarug et al., 2002). The International Agency for Research on Cancer (IARC) has classified cadmium as a human carcinogen, based on an elevated incidence of lung cancer and mortality among those who had elevated workplace exposure to cadmium through inhalation (IARC, 1993). The role played by cadmium in lung cancer has been substantiated by a 1.7-, 4.2- and 1.57-fold increase in lung cancer risk observed in the 15-year Belgian cohort among those with; 2-fold increase in body burden of cadmium, those living in a “high” exposure area, and 2-fold increase in soil-cadmium content, respectively (Nawrot et al., 2006). In this mini-review, we will summarize our work focussing on benzo(a)pyrene-7,8-diol-9,10-epoxide-N2-deoxyguanosine (BPDE-dG) adduct in human bronchial cells produced from exposure to BP and its possible contribution to the lung carcinogenesis in those who smoke. We will then discuss the potential role played by liver, dietary BP and cadmium in lung cancer in smokers. Lastly, we will suggest approaches to reducing the formation of BPDE-dG adduct as possible ways to reduce lung cancer risk from concurrent exposure to BP and cadmium.

Section snippets

Exposure to benzo[a]pyrene and lung cancer

BP is a highly carcinogenic polycyclic aromatic hydrocarbon (PAH) that has long been suspected to be involved in the etiology of lung cancer (Hecht, 2003). The focus on BP is partly due to the intense research activity on this carcinogen, beginning in the 1930s and reaching fever pitch in the 1970s to 1980s. BP is a strong, locally acting carcinogen, and tobacco-smoke fractions enriched with BP are proven carcinogenic (Deutsch-Wenzel et al., 1983). A typical BP level is less than 10 ng per

Evidence for role of BPDE-dG adduct in lung cancer

We and others attempted to detect BPDE-dG adduct in samples of non-tumorous human lung parenchyma from smokers vs. non-smokers, but the levels of BPDE-dG adduct in most samples were under the limits of detection (Boysen and Hecht, 2003, Rojas et al., 1998, Rojas et al., 2004). Arif et al. (2006) re-analyzed human lung parenchyma samples with 32P-post-labeling/thin layer chromatography (TLC) and they showed that the BPDE-dG adduct on diagonal radioactive zones were not related to PAHs or

Cytochromes P450 and the formation of BPDE-dG adduct

Cytochrome P450 (CYP) is a mixture of enzymes present in human and animal tissues, and indeed in all eukaryotes and prokaryotes (http://drnelson.utmem.edu/CytochromeP450.html). These enzymes have an absolutely conserved cysteine residue in their protein primary amino acid sequence. The cysteine thiolate group allows for binding the heme prosthetic group of these enzymes. This determines the particular characteristic of the protein's absorbance spectrum with a peak at 450 nm and hence the term

Free radicals in cigarette smoke enhances the formation of BPDE-dG adduct

Increasing evidence suggests the causal significance of tobacco-derived free radicals in lung cancer induction (Nakayama et al., 1985, Pryor, 1997). Each puff of cigarette smoke forms over 10 trillion free radicals, which may contribute to both initiation and promotion of various forms of human tumor because of repeated ROS attacks on cellular macromolecules. Nitric oxide and an equilibrium mixture of hydroquinones, semiquinones and quinones were postulated to be the major free radical species

Liver and the formation of BPDE-dG adduct in the lung

Liver to lung transport of the stable (−)-BP-7,8-diol has been shown to occur in mice injected with BP (Wall et al., 1985). This observation supports the conclusion that liver export of BP-7,8-diol to the lung could be another critical event in lung chemical carcinogenesis (Alexandrov et al., 2006). BPDE was detectable in the blood samples (Ginsberg and Atherholt, 1990) while BPDE-DNA adducts were ubiquitously and persistently present in tissues of BP-treated rodents (Kulkarni and Anderson, 1984

High abundance of BPDE-dG in bronchial epithelial cells from lung cancer patients

We have reported the presence of BPDE-dG in all pure isolates of bronchial epithelial cells from lung cancer patients both smokers and non-smokers (Rojas et al., 2004). Considerably higher adduct levels were detected in bronchial epithelial cells (75.8 ± 38.8 adducts/108 nucleotides) than in parenchyma tissue (0.9 ± 1.5 adducts/108 nucleotides). Thus BPDE-dG adducts concentrates almost exclusively in the target bronchial epithelial cells from which the onset of bronchial carcinoma might occur.

Cadmium exposure and BP-induced lung cancer

Cadmium content of the tobacco from various brands of cigarettes made in China varied between 1.3 and 2 μg/g whereas it ranged from 0.9 to 1.2 μg/g in imported brands (Jin et al., 1999). This translates to 0.7–1 μg cadmium per cigarette, assuming each cigarette comprises 0.5 g tobacco. Cadmium oxide in tobacco smoke is highly bioavailable-approximately 10% of cadmium oxide inhaled is deposited in lung tissues while another 30–40% is absorbed into systemic blood circulation of smokers. Satarug et

Inhibition of BP-induced lung tumorigenesis via reduction of BPDE-dG adduct formation

The occurrence of BPDE-dG adduct have been used for more than 10 years in molecular and analytical epidemiologic investigations to establish risk for cancer initiation in the lung and other organs such as the pancreas and large bowel. Such occurrence of BPDE-dG adduct reflects the earliest event critical in the pathogenesis of cancer. The BPDE-dG adduct cannot however serve as an indicator of disease progression. We propose the use of the BPDE-dG as a biomarker in the validation of preventative

Concluding remarks

Lung cancer develops after chronic exposure to BP and cadmium in every puff of a cigarette as well as from dietary and other environmental sources. Formation of BPDE-DNA adduct after CYP-mediated metabolic activation of BP in liver and lung and the removal of BPDE-DNA adduct occur constantly and undoubtedly reach a steady state after 20–30 years of smoking. The resulting cumulative DNA damage is consistent with mutational changes in multiple genes that are seen in lung tumors as normal tissues

Conflict of interest statement

None.

Acknowledgement

Funding: We thank Dr George Kruzynski for the edit of this review. Dr. S. Satarug was a recipient of the Reverse Brain Drain Award, Thailand's National Science and Technology Development Agency and Commission for Higher Education.

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