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Review

Biomarkers of Induced Active and Passive Smoking Damage

by
Maura Lodovici
* and
Elisabetta Bigagli
Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2009, 6(3), 874-888; https://doi.org/10.3390/ijerph6030874
Submission received: 23 December 2008 / Accepted: 20 February 2009 / Published: 26 February 2009
(This article belongs to the Special Issue Tobacco Smoking and Public Health)
Versions Notes

Abstract

:
In addition to the well-known link between smoking and lung cancer, large epidemiological studies have shown a relationship between smoking and cancers of the nose, oral cavity, oropharynx, larynx, esophagus, pancreas, bladder, kidney, stomach, liver, colon and cervix, as well as myeloid leukemia. Epidemiological evidence has reported a direct link between exposure of non-smokers to environmental tobacco smoke and disease, most notably, lung cancer. Much evidence demonstrates that carcinogenic-DNA adducts are useful markers of tobacco smoke exposure, providing an integrated measurement of carcinogen intake, metabolic activation, and delivery to the DNA in target tissues. Monitoring accessible surrogate tissues, such as white blood cells or bronchoalveolar lavage (BAL) cells, also provides a means of investigating passive and active tobacco exposure in healthy individuals and cancer patients. Levels of DNA adducts measured in many tissues of smokers are significantly higher than in non-smokers. While some studies have demonstrated an association between carcinogenic DNA adducts and cancer in current smokers, no association has been observed in ex or never smokers. The role of genetic susceptibility in the development of smoking related-cancer is essential. In order to establish whether smoking-related DNA adducts are biomarkers of tobacco smoke exposure and/or its carcinogenic activity we summarized all data that associated tobacco smoke exposure and smoking-related DNA adducts both in controls and/or in cancer cases and studies where the effect of genetic polymorphisms involved in the activation and deactivation of carcinogens were also evaluated. In the future we hope we will be able to screen for lung cancer susceptibility by using specific biomarkers and that subjects of compared groups can be stratified for multiple potential modulators of biomarkers, taking into account various confounding factors.

1. Introduction

Tobacco is the single most preventable cause of death in the world today, it has been estimated to have killed more than five million people in 2008 and will be responsible for the death of more than eight million by 2030 [1]. While many countries have adopted consistent policies against its use in public places, there are still approximately 1.3 billion smokers in the world and hundreds of millions of smokeless tobacco users. Cigarette smoking causes 30% of all cancer mortality in developed countries, and smokeless tobacco use is an important cause of cancer, particularly in southern Asia [2]. Tobacco smoke contains more than 4,000 chemicals and some of them are carcinogens. The strongest carcinogens present in tobacco smoke are polycyclic aromatic hydrocarbons (PAH), N-nitrosamines, aromatic amines, aldehydes, benzene and butadiene. Cigarette smoke products can be divided into particulate and gas phases. The particulate phase contains nicotine, nitrosamines [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone], N-nitrosonornicotine, metals, polycyclic aromatic hydrocarbons (PAH) and carcinogenic amines (4-aminobiphenyl). The gas phase contains carbon monoxide, carbon dioxide, benzene, ammonia, formaldehyde, hydrogen cyanide, N-nitroso-dimethylamine and N-nitrosodiethylamine [3].
In addition to the well-known link between smoking and lung cancer, large epidemiological studies have shown a relationship between smoking and cancers of the nose, oral cavity, oropharynx, hypopharynx, larynx, esophagus, pancreas, bladder, kidney, stomach, liver, colon, cervix as well as myeloid leukemia [4]. Cigarette smoking predisposes the individual to several different clinical atherosclerotic syndromes, including stable angina, acute coronary syndromes, aortic and peripheral atherosclerosis sudden death, and stroke [5].

2. Environmental Tobacco Smoke

In 1986 the Surgeon General of the United States published a landmark report, based on epidemiological evidence, asserting a direct link between exposure of non-smokers to environmental tobacco smoke and disease, most notably, lung cancer [6]. In the same year, the National Academy of Sciences reported similar conclusion regarding the adverse effects of exposure to environmental tobacco smoke [7]. In 1997, the California Environmental Protection Agency published the final draft of a report regarding all known health effects of exposure to environmental tobacco smoke, including ischemic heart disease, lung cancer and bronchitis [8]. More than 50 studies on passive smoking and lung cancer risk in never smokers, especially spouses of smokers, have been carried out and published within the past 25 years. These studies show that there is a statistically significant and consistent association between lung cancer risk in spouses of smokers and second-hand smoke from the spouse who smokes. This excess risk is on the order of 20% for women and 30% for men. The excess risk increases with increasing exposure [9]. It has been described that there is an increased risk of lower respiratory diseases in children of smoking parents and an increased risk of asthma [8]. The results from these reports have increased the debate on smoking and environmental tobacco smoke’s health impact on non-smokers and set off controversy regarding smoking in the workplace and public buildings. Tobacco combustion results in the formation of mainstream smoke and sidestream smoke. Cigarette smoke that is drawn through the tobacco into an active smoker’s mouth is known as mainstream smoke. Sidestream cigarette smoke is the smoke emitted from the burning end of a cigarette.
Environmental tobacco smoke results from the combination of sidestream smoke (85%) and a small fraction of exhaled mainstream smoke (15%) from smokers. For the most part, the chemical compositions of sidestream smoke and mainstream smoke are qualitatively similar and most toxic carcinogens are present in both of them but in different concentrations because of ageing and dilution with ambient air. Smokers who actively inhale very large doses of mainstream smoke-carcinogens, have a higher intake of carcinogens than environmental tobacco smoke-exposed individuals [10,11].

3. Environmental Exposure, Internal Dose and Biologically Effective Dose

Molecular biomarkers are typically indicators of exposure effect or susceptibility [12]. A biomarker of exposure indicates the presence of exposure to an environmental agent while a biomarker of effect indicates the presence of a biological response to exposure to an environmental agent. Biomarkers thus have significant potential in clarifying the relationship between environmental agents and disease [13]. A biomarker of exposure requires measurement of toxicant levels in the environment and characterization of the individual presence, and interaction with that environment. But, a complexity arising from the use of ambient measurements to determine exposure status of individuals is the heterogeneous nature of most environmental contaminations. These measurements should be added to a system that integrates fluctuating exposures over time and relates time of exposure to dose. Given these problems of extrapolating ambient measurements to specific individual exposure, it has been well recognized that measures of the internal dose of a specific agent provide a clearer demonstration that a toxicant has been absorbed and possibly distributed in the body. Internal dose measurements are an effective identification of previous exposure, however, they do not provide evidence that toxicological damage has occurred. Among the various possible biomarkers of cancer risk is the measurement of carcinogen-DNA adducts, which are direct products of, or surrogate markers for, damage to critical macromolecular targets. DNA adduct measurement provides an integrated measurement of carcinogen intake, metabolic activation and delivery to the target macromolecule in target tissues (biologically effective dose) [14].
Many different type of analytical techniques have been developed to measure DNA adducts, including 32P-postlabeling with or without nuclease P1, immunoassay using antibodies to DNA adducts, physicochemical properties of adducts, such as fluorescence and mass spectrometry. Although each methodology has very different detection endpoints, the results obtained show a high quantitative similarity [15–17].

4. Biomarkers of Active and Passive Smoke Exposure

Since the aim of this review is the evaluation of carcinogenic-DNA adducts as biomarkers of tobacco smoke exposure and its carcinogenic activity we reported studies that measured smoking-related DNA adducts as biomarkers of tobacco smoke exposure both in cancer cases and healthy smokers and non-smoker subjects [18–25]. The results obtained from these studies demonstrate that, as reported in Table 1A, higher DNA adduct levels were found for tobacco smoke exposure (lung, bronchus, uterine cervix. etc.) in target organs from smokers than non smokers. Some of these authors also found a correlation between adduct levels and smoke exposure [18,20]. In one study a good correlation was also found between DNA adducts and benzo(a)pyrene levels measured in lung tissue from smokers [24].
When a surrogate tissue (white blood cells) was used, different results were observed from various laboratories. Some studies indicated a correlation between adduct levels in blood cells and lung as well as higher DNA adducts in smokers than in non smokers [26–28], while others demonstrate that white blood cells are not a good surrogate tissue [29,30] and still others that similar DNA adduct levels occur in blood cells from smokers and non-smokers [31,32], using 8-hydroxydeoxyguanosine as a marker of oxidative DNA damage [25,33]. With the same method other authors [34,35] report a significant increase in oxidative DNA damage in leukocytes from subjects exposed to environmental tobacco smoke and a correlation between DNA damage and tobacco exposure, measured by plasma cotinine levels. Using DNA isolated from bronchoalveolar lavage (BAL) cells, DNA adduct levels were found to be significantly higher in smokers than in non-smokers [36–39]. But in 1992 Alexandrov et al. [20] published an important observation demonstrating that benzo[a]pyrenediol epoxide-DNA adducts were positively correlated with CYP1A1 enzyme activity in lung tissue of smokers. Later, many researchers focused their attention on the effect of genetic polymorphisms involved in the activation and deactivation of carcinogens on risk damage to tobacco exposure.
In our review we also considered studies that took into account the effect of genetic polymorphisms involved in the activation and deactivation of carcinogens on DNA adduct levels. For this reason, since major classes of carcinogens present in tobacco smoke are converted into DNA reactive metabolites by cytochrome P450-related enzymes, we reported studies that evaluated the effect of polymorphisms of CYPs in humans, alone or in addition to phase II enzymes, particularly glutathione S-transferase (GST) on DNA adduct levels. These data are summarized in Table 1B. CYP1A1 is a phase I enzyme involved in the metabolic activation of aromatic amines and PAH and may affect the metabolism of environmental carcinogens and alter susceptibility to lung cancer. On the contrary, GST is a large family of phase II enzyme involved in xenobiotic detoxification. Butkiewicz et al. [40] found higher adduct levels in lung tissue from smokers lung cancer than non-smokers and a significant relationship between high adduct levels and the combined GSTM1 (null) and CYP1A1 polymorphic genotype. Similarly, Lewis et al. [41] reported that adduct levels tended to be higher in individuals with GSTM1 null, GSTT1 null or GSTP1 wt genotypes in bronchial lavage samples while Peluso et al. [42] found no significant effect on DNA adducts and genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 in 55 nasal brushing and bronchoscopies. Texeira et al. [43] reported that lymphocytes from smokers had significantly higher DNA adducts than non-smokers with a good correlation between the levels of DNA adducts and the number of cigarettes smoked. The levels of DNA adducts in smokers is dependent on polymorphisms of CYP1A1 MspI. In fact, the allele variant of CYP1A1 MspI had DNA adducts about two-fold higher than CYP1A1 MpsI with no allele variant, but no effect was observed for the GST genotypes studied [43]. On the contrary, DNA adduct levels, adjusted for the number of cigarettes smoked per day, were found to be significantly higher in mononuclear blood cells from individuals with GSTM1 null than those with GSTM1 active [44]. In one study where smokers were divided into a high-risk group with CYP1A1 MspI and/or exon 7 Ile462Val allele variants, glutathione S-transferase M1 (GSTM1) null allele and wt glutathione S-transferase P1 (GSTP1), and a low-risk group (wt CYP1A1) and higher deactivation capacity (active GSTM1, GSTP1 Ile105Val allele), significantly lower BPDE-DNA adduct levels were reported in low-risk group [45]. Interestingly, Van Schooten et al., [46] found that MPO mutant genotypes are associated with reduced MPO activity in BAL fluid and reduced smoking-related DNA adduct levels in BAL cells in a gene-dose manner. Ketelslegers et al. [47] observed that GSTM1*0, mEH*2, and GPX1*1 are the most relevant polymorphisms for lymphocytic DNA adduct levels in smokers. Individuals having four risk alleles for these three genes had higher DNA adduct levels than individuals not possessing these particular risk alleles. However, recently Mollerup et al. [48] found lung DNA adducts highly related to CYP1A1 expression, but irrespective of smoking-status in cancer cases.

5. Biomarkers of Tobacco Smoke Carcinogenic Activity

In the molecular epidemiological literature carcinogen-DNA adducts are referred to as biomarkers of the biologically effective dose of a carcinogen and thus biomarkers of cancer risk. Carcinogen-DNA adducts represent the amount of carcinogen absorbed by the body that is not detoxificated, that is bound to cellular macromolecules and has not been repaired [49,50]. There is clear evidence that carcinogen-DNA adducts can reflect exposure to xenobiotics and there is clear mechanistic evidence that carcinogen-DNA adduct formation is a key to chemical carcinogenesis [51–53]. Recently, a number of reviews on carcinogen-DNA adducts mention epidemiological studies that have investigated whether increased adduct levels are associated with cancer incidence [54–56]. A minority of these reports takes into account the limitations of this literature from an epidemiological point of view, eg. short half-lives of adducts, multiple exposures, weak effects and interactions with genetic susceptibility [53,55]. Veglia et al. [55] conducted a meta-analysis of active smoking and cancer, including five studies of lung cancer [57–60,27], one of oral cancer [61] and one of bladder cancer [62] in which bulky DNA adducts were measured. They found a significant relationship between bulky DNA adducts and cancer in current smokers, while no association was observed in ex- and never smokers. The methods and results of the individual studies analyzed in the meta-analysis of Veglia et al. [55] are reported in Table 2A.
Hou et al. [58] found no association between carcinogen-DNA adducts and cancer in smokers but the only matching factor accounted for in these analyses was smoking. However, it was previously reported that failure to fully account for matching in a case-control study tends to bias results toward the null [63]. The same bias was also present in the study of Vulimiri et al. [59] that found significantly higher carcinogen-DNA adducts in cases than in controls, although no statistical control for the matching variables was considered and the observed difference may be an underestimate of the effective differences. In addition to the studies included in the meta-analysis by Veglia et al. [55] data obtained from three other studies have been published on smoking-related cancers and carcinogen-DNA adducts (Table 2A).
Adduct levels in bladder tissue were measured by 32P-postlabeling by Benhamou et al., [64] and no significant association was found between adducts and bladder cancer case-control status. However, smoking status was not taken into account in the data analysis. In the study of Peluso et al. [65] a relationship was observed between detectable adducts and lung cancer risk among never-smokers with OR = 4.04 (1.06–15.42), while adduct levels were not significantly associated with lung cancer in former-smokers. For the other cancers no association with detectable adduct levels was found [64]. On the contrary, Bak et al. [66] measured adduct levels in white blood cells from 255 randomly selected subjects considering sex, year of birth and smoking duration and demonstrated that among current smokers high adducts were significantly associated with lung cancer risk (incidence rate ratio (IRR) = 1.61 (1.04–2.49) while high adduct levels, defined as being above the median level of the controls, were not.
Although tobacco smoking is a well established risk factor for tobacco-related cancers, not all of those who have been exposed will develop disease, suggesting that there is individual variation in cancer susceptibility in the general population and that genetic polymorphisms may modulate the association observed between exposure and cancer [67,3] Some of the most widely studied polymorphic loci are those coding for phase I and II enzymes involved in the activation and conjugation of carcinogens from tobacco smoke. The most frequently studied include CYP1A1, microsomal epoxide hydrolase 1 (mEH/EPHX1), myeloperoxidase (MPO), NAD (P) H quinone oxidoreductase 1 (NQO1) and the glutathione S-transferases (M1, P1 and T1), although others have also been studied [3]. Individuals with some genetic variants in the GST and CYP genes are reported to have different levels of PAH-DNA adducts in their lung tissue than those with wt genotype, and genetic variants have been extensively studied as candidates for lung cancer susceptibility as summarized in Table 2B. Ryberg et al. [68], analyzing 70 lung cancers, found higher DNA adduct levels in patients with the null GSTM1 genotype than in those with at least one intact GSTM1 allele. Moreover, significantly lower adduct levels were found in patients with the polymorphic GSTP1 genotype (with higher affinity for PAH-diolepoxides) compared to those with the wild type GSTP1 genotype. The same results were obtained by Royas et al. [69] who found a highly significant difference in DNA adduct levels between lung cancer patients with GSTM1 null and those with GSTM1 active genotype. On the contrary, Schoket et al. [70] reported no association between the combined CYP1A1 MspI and GSTM1 genotypes and DNA adduct levels in bronchial tissue from 150 pulmonary surgery patients (126 with lung cancer). In one study analyzing 73 cancer cases Cheng et al. [60] found significantly high adducts levels than controls (33), but no association was observed with CYP1A1Msp1 or GSTM1 genotypes; on the contrary data reported by Li et al. [71] demonstrated an association between high adducts and CYP1A1 polymorphism in pancreatic cancer patients.

6. Conclusions

The available data obtained from past decades show that DNA adduct formation is a key step in tobacco carcinogenesis, although the experimental evidence that carcinogen-DNA adducts are useful as biomarkers for evaluating the association between tobacco exposure and cancer risk is not always recognized. Hopefully in the future we will be able to screen individuals for cancer susceptibility by using specific biomarkers (for precise DNA adducts and metabolic polymorphisms) and then subjects can be stratified for multiple potential modulators of biomarkers, taking into account various confounding factors.

References

  1. Bettcher, DW; Sanda, LS. Clinical cancer control and prevention. Eliminating tobacco-induced cancers: a worldwide challenge. Ann. Oncol 2008, 19, 230–233. [Google Scholar]
  2. Hecht, SS. Progress and challenges in selected areas of tobacco carcinogenesis. Chem. Res. Toxicol 2008, 21, 160–171. [Google Scholar]
  3. Taioli, E. Gene-environment interaction in tobacco-related cancers. Carcinogenesis 2008, 29, 1467–1474. [Google Scholar]
  4. Jemal, A; Thun, MJ; Ries, LA; Howe, HL; Weir, HK; Center, MM; Ward, E; Wu, XC; Eheman, C; Anderson, R; Ajani, UA; Kohler, B; Edwards, BK. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J. Natl. Cancer Ins 2008, 100, 1672–1694. [Google Scholar]
  5. Ambrose, JA; Barua, RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J. Am. Coll. Cardiol 2004, 43, 1731–1737. [Google Scholar]
  6. IDEM. The health consequences of involuntary smoking: a report of the Surgeon General; Publication N. DHHS (CDC) 87-(8398). Government Printing Office: Washington DC, USA, 1986. [Google Scholar]
  7. National Research Council. Committee on passive smoking; National Academy Press: Washington DC, USA, 1986. [Google Scholar]
  8. California Environmental Protection Agency. Health effects of exposure to environmental tobacco smoke. Final Draft. California Environmental Protection Agency, 1997. [Google Scholar]
  9. IARC (International Agency for Research on Cancer). Tobacco smoking and involuntary smoking. ARC Monographs on the Evaluation of Carcinogenic Risks to Humans.
  10. Lodovici, M; Akpan, V; Evangelisti, C; Dolara, P. Sidestream tobacco smoke as the main predictor of exposure to polycyclic aromatic hydrocarbons. J. Appl. Toxicol 2004, 24, 277–281. [Google Scholar]
  11. Besaratinia, A; Pfeifer, GP. Second-hand smoke and human lung cancer. Lancet Oncol 2008, 9, 657–666. [Google Scholar]
  12. Biological markers in environmental health research. Committee on Biological Markers of the National Research Council. Environ. Health Perspect 1987, 74, 3–9. [Google Scholar]
  13. Wogan, GN. Molecular epidemiology in cancer risk assessment and prevention: recent progress and avenues for future research. Environ. Health Perspec 1992, 98, 167–178. [Google Scholar]
  14. Groopman, JD; Kensler, TW; Links, JM. Molecular epidemiology and human risk monitoring. Toxicol Lett 1995, 82–83, 763–769. [Google Scholar]
  15. Phillips, DH. Detection of DNA modifications by the 32P-postlabelling assay. Mutat Res 1997, 378, 1–12. [Google Scholar]
  16. Wild, CP; Pisani, P. Carcinogen DNA and protein adducts as biomarkers of human exposure in environmental cancer epidemiology. Cancer Detect. Prev 1998, 22, 273–283. [Google Scholar]
  17. Poirier, MC; Santella, RM; Weston, A. Carcinogen macromolecular adducts and their measurement. Carcinogenesis 2000, 21, 353–359. [Google Scholar]
  18. Phillips, DH; Hewer, A; Martin, CN; Garner, RC; King, MM. Correlation of DNA adduct levels in human lung with cigarette smoking. Nature 1988, 336, 790–792. [Google Scholar]
  19. Talaska, G; Schamer, M; Skipper, P; Tannenbaum, S; Caporaso, N; Unruh, L; Kadlubar, FF; Bartsch, H; Malaveille, C; Vineis, P. Detection of carcinogen-DNA adducts in exfoliated urothelial cells of cigarette smokers: association with smoking, hemoglobin adducts, and urinary mutagenicity. Cancer Epidemiol. Biomarkers Prev 1991, 1, 61–66. [Google Scholar]
  20. Alexandrov, K; Rojas, M; Geneste, O; Castegnaro, M; Camus, AM; Petruzzelli, S; Giuntini, C; Bartsch, H. An improved fluorometric assay for dosimetry of benzo(a)pyrene diolepoxide-DNA adducts in smokers' lung: comparisons with total bulky adducts and aryl hydrocarbon hydroxylase activity. Cancer Res 1992, 52, 6248–6253. [Google Scholar]
  21. Simons, AM; Múgica van, Herckenrode C; Rodriguez, JA; Maitland, N; Anderson, M; Phillips, DH; Coleman, DV. Demonstration of smoking-related DNA damage in cervical epithelium and correlation with human papillomavirus type 16, using exfoliated cervical cells. Br. J. Cancer 1995, 71, 246–249. [Google Scholar]
  22. Andreassen, A; Kure, EH; Nielsen, PS; Autrup, H; Haugen, A. Comparative synchronous fluorescence spectrophotometry and 32P-postlabeling analysis of PAH-DNA adducts in human lung and the relationship to TP53 mutations. Mutat. Res 1996, 368, 275–282. [Google Scholar]
  23. Wang, M; Abbruzzese, JL; Friess, H; Hittelman, WN; Evans, DB; Abbruzzese, MC; Chiao, P; Li, D. DNA adducts in human pancreatic tissues and their potential role in carcinogenesis. Cancer Res 1998, 58, 38–41. [Google Scholar]
  24. Lodovici, M; Akpan, V; Giovannini, L; Migliani, F; Dolara, P. Benzo[a]pyrene diol-epoxide DNA adducts and levels of polycyclic aromatic hydrocarbons in autoptic samples from human lungs. Chem. Biol. Interact 1998, 116, 199–212. [Google Scholar]
  25. Asami, S; Manabe, H; Miyake, J; Tsurudome, Y; Hirano, T; Yamaguchi, R; Itoh, H; Kasai, H. Cigarette smoking induces an increase in oxidative DNA damage, 8-hydroxydeoxyguanosine, in a central site of the human lung. Carcinogenesis 1997, 18, 1763–1766. [Google Scholar]
  26. Savela, KK; Hemminki, K. DNA adducts in lymphocytes and granulocytes of smokers and nonsmokers detected by the 32P-postlabelling assay. Carcinogenesis 1991, 12, 503–508. [Google Scholar]
  27. Tang, D; Phillips, DH; Stampfer, M; Mooney, LA; Hsu, Y; Cho, S; Tsai, WY; Ma, J; Cole, KJ; Shé, MN; Perera, FP. Association between carcinogen-DNA adducts in white blood cells and lung cancer risk in the physicians health study. Cancer Res 2001, 61, 6708–6712. [Google Scholar]
  28. Wiencke, JK; Kelsey, KT; Varkonyi, A; Semey, K; Wain, JC; Mark, E; Christiani, DC. Correlation of DNA adducts in blood mononuclear cells with tobacco carcinogen-induced damage in human lung. Cancer Res 1995, 55, 4910–4914. [Google Scholar]
  29. Van Schooten, FJ; Hillebrand, MJ; van Leeuwen, FE; van Zandwijk, N; Jansen, HM; den Engelse, L; Kriek, E. Polycyclic aromatic hydrocarbon–DNA adducts in white blood cells from lung cancer patients: no correlation with adduct levels in lung. Carcinogenesis 1992, 13, 987–993. [Google Scholar]
  30. Van Schooten, FJ; Godschalk, RW; Breedijk, A; Maas, LM; Kriek, E; Sakai, H; Wigbout, G; Baas, P; Van't Veer, L; Van Zandwijk, N. 32P-postlabelling of aromatic DNA adducts in white blood cells and alveolar macrophages of smokers: saturation at high exposures. Mutat. Res 1997, 378, 65–75. [Google Scholar]
  31. Yang, K; Airoldi, L; Pastorelli, R; Restano, J; Guanci, M; Hemminki, K. Aromatic DNA adducts in lymphocytes of humans working at high and low traffic density areas. Chem. Biol. Interact 1996, 101, 127–136. [Google Scholar]
  32. Lodovici, M; Akpan, V; Casalini, C; Nencini, L; Pinzauti, M; Marcoccia, M; Dolara, P. Benzo(a)pyrene diol-epoxide-DNA adduct levels and aryl hydrocarbon hydroxylase (AHH) in human white blood cells from smokers and non-smokers. Biomarkers 1999, 4, 272–280. [Google Scholar]
  33. Lodovici, M; Casalini, C; Cariaggi, R; Michelucci, L; Dolara, P. Levels of 8-hydroxydeoxyguanosine as a marker of DNA damage in human leukocytes. Free Radic. Biol. Med 2000, 28, 13–17. [Google Scholar]
  34. Howard, DJ; Ota, RB; Briggs, LA; Hampton, M; Pritsos, CA. Oxidative stress induced by environmental tobacco smoke in the workplace is mitigated by antioxidant supplementation. Cancer Epidemiol. Biomarkers Prev 1998, 7, 981–988. [Google Scholar]
  35. Lodovici, M; Caldini, S; Luceri, C; Bambi, F; Boddi, V; Dolara, P. Active and passive smoking and lifestyle determinants of 8-oxo-7,8-dihydro-2′-deoxyguanosine levels in human leukocyte DNA. Cancer Epidemiol. Biomarkers Prev 2005, 14, 2975–2977. [Google Scholar]
  36. Izzotti, A; Rossi, GA; Bagnasco, M; De Flora, S. Benzo[a]pyrene diolepoxide-DNA adducts in alveolar macrophages of smokers. Carcinogenesis 1991, 12, 1281–1285. [Google Scholar]
  37. Sherman, MP; Aeberhard, EE; Wong, VZ; Simmons, MS; Roth, MD; Tashkin, DP. Effects of smoking marijuana, tobacco or cocaina alone or in combination on DNA damage in human alveolar macrophages. Life Sci 1995, 56, 2201–2207. [Google Scholar]
  38. Godschalk, RW; Maas, LM; Van Zandwijk, N; van 't Veer, LJ; Breedijk, A; Borm, PJ; Verhaert, J; Kleinjans, JC; van Schooten, FJ. Differences in aromatic-DNA adduct levels between alveolar macrophages and subpopulations of white blood cells from smokers. Carcinogenesis 1998, 19, 819–825. [Google Scholar]
  39. Piipari, R; Savela, K; Nurminen, T; Hukkanen, J; Raunio, H; Hakkola, J; Mäntylä, T; Beaune, P; Edwards, RJ; Boobis, AR; Anttila, S. Expression of CYP1A1, CYP1B1 and CYP3A and polycyclic aromatic hydrocarbon-DNA adduct formation in bronchoalveolar macrophages of smokers and non-smokers. Int. J. Cancer 2000, 86, 610–616. [Google Scholar]
  40. Butkiewicz, D; Cole, KJ; Phillips, DH; Harris, CC; Chorazy, M. GSTM1, GSTP1, CYP1A1 and CYP2D6 polymorphisms in lung cancer patients from an environmentally polluted region of Poland: correlation with lung DNA adduct levels. Eur. J. Cancer Prev 1999, 8, 315–323. [Google Scholar]
  41. Lewis, SJ; Cherry, NM; Niven, RM; Barber, PV; Povey, AC. Associations between smoking, GST genotypes and N7-methylguanine levels in DNA extracted from bronchial lavage cells. Mutat. Res 2004, 559, 11–18. [Google Scholar]
  42. Peluso, M; Neri, M; Margarino, G; Mereu, C; Munnia, A; Ceppi, M; Buratti, M; Felletti, R; Stea, F; Quaglia, R; Puntoni, R; Taioli, E; Garte, S; Bonassi, S. Comparison of DNA adduct levels in nasal mucosa, lymphocytes and bronchial mucosa of cigarette smokers and interaction with metabolic gene polymorphisms. Carcinogenesis 2004, 25, 2459–2465. [Google Scholar]
  43. Teixeira, JP; Gaspar, J; Martinho, G; Silva, S; Rodrigues, S; Mayan, O; Martin, E; Farmer, PB; Rueff, J. Aromatic DNA adduct levels in coke oven workers: correlation with polymorphisms in genes GSTP1, GSTM1, GSTT1 and CYP1A1. Mutat. Res 2002, 517, 147–155. [Google Scholar]
  44. Godschalk, RW; Dallinga, JW; Wikman, H; Risch, A; Kleinjans, JC; Bartsch, H; van Schooten, FJ. Modulation of DNA and protein adducts in smokers by genetic polymorphisms in GSTM1,GSTT1, NAT1 and NAT2. Pharmacogenetics 2001, 11, 389–398. [Google Scholar]
  45. Lodovici, M; Luceri, C; Guglielmi, F; Bacci, C; Akpan, V; Fonnesu, ML; Boddi, V; Dolara, P. Benzo(a)pyrene diolepoxide (BPDE)-DNA adduct levels in leukocytes of smokers in relation to polymorphism of CYP1A1, GSTM1, GSTP1, GSTT1, and mEH. Cancer Epidemiol. Biomarkers Prev 2004, 13, 1342–1348. [Google Scholar]
  46. Van Schooten, FJ; Boots, AW; Knaapen, AM; Godschalk, RW; Maas, LM; Borm, PJ; Drent, M; Jacobs, JA. Myeloperoxidase (MPO) -463G->A reduces MPO activity and DNA adduct levels in bronchoalveolar lavages of smokers. Cancer Epidemiol. Biomarkers Prev 2004, 13, 828–833. [Google Scholar]
  47. Ketelslegers, HB; Gottschalk, RW; Knaapen, AM; van Schooten, FJ; Vlietinck, RF; Kleinjans, JC; van Delft, JH. Interindividual variations in DNA adduct levels assessed by analysis of multiple genetic polymorphisms in smokers. Cancer Epidemiol. Biomarkers Prev 2006, 15, 624–629. [Google Scholar]
  48. Mollerup, S; Berge, G; Baera, R; Skaug, V; Hewer, A; Phillips, DH; Stangeland, L; Haugen, A. Sex differences in risk of lung cancer: Expression of genes in the PAH bioactivation pathway in relation to smoking and bulky DNA adducts. Int. J. Cancer 2006, 119, 741–744. [Google Scholar]
  49. Perera, FP; Poirier, MC; Yuspa, SH; Nakayama, J; Jaretzki, A; Curnen, MM; Knowles, DM; Weinstein, IB. A pilot project in molecular cancer epidemiology: determination of benzo[a]pyrene-DNA adducts in animal and human tissues by immunoassays. Carcinogenesis 1982, 3, 1405–1410. [Google Scholar]
  50. Rothman, N; Shields, PG; Poirier, MC; Harrington, AM; Ford, DP; Strickland, PT. The impact of glutathione s-transferase M1 and cytochrome P450 1A1 genotypes on white-blood-cell polycyclic aromatic hydrocarbon-DNA adduct levels in humans. Mol. Carcinog 1995, 14, 63–68. [Google Scholar]
  51. Marshall, CJ; Vousden, KH; Phillips, DH. Activation of c-Ha-ras-1 proto-oncogene by in vitro modification with a chemical carcinogen, benzo(a)pyrene diol-epoxide. Nature 1984, 310, 586–589. [Google Scholar]
  52. Vousden, K; Bos, JL; Marshall, CJ; Phillips, DH. Mutations activating human c-Ha-ras1 protooncogene (HRAS) induced by chemical carcinogens and depurination. Proc. Natl. Acad. Sci 1986, 83, 1222–1226. [Google Scholar]
  53. Hemminki, K; Koskinen, M; Rajaniemi, H; Zhao, C. Dna adducts, mutations, and cancer 2000. Regul. Toxicol. Pharmacol 2000, 32, 264–275. [Google Scholar]
  54. Vineis, P; Perera, F. DNA adducts as markers of exposure to carcinogens and risk of cancer. Int. J. Cancer 2000, 88, 325–328. [Google Scholar]
  55. Veglia, F; Matullo, G; Vineis, P. Bulky DNA adducts and risk of cancer: a meta-analysis. Cancer Epidemiol. Biomarkers Prev 2003, 12, 157–160. [Google Scholar]
  56. Phillips, DH. DNA adducts as markers of exposure and risk. Mutat. Res 2005, 577, 284–292. [Google Scholar]
  57. Tang, D; Santella, RM; Blackwood, AM; Young, TL; Mayer, J; Jaretzki, A; Grantham, S; Tsai, WY; Perera, FP. A molecular epidemiological case-control study of lung cancer. Cancer Epidemiol. Biomark Prev 1995, 4, 341–346. [Google Scholar]
  58. Hou, SM; Yang, K; Nyberg, F; Hemminki, K; Pershagen, G; Lambert, B. Hprt mutant frequency and aromatic DNA adduct level in nonsmoking and smoking lung cancer patients and population controls. Carcinogenesis 1999, 20, 437–444. [Google Scholar]
  59. Vulimiri, SV; Wu, X; Baer-Dubowska, W; Andrade, MD; Detry, M; Spitz, MR; DiGiovanni, J. Analysis of aromatic DNA adducts and 7,8-dihydro-8-oxo-2’ deoxyguanosine in lymphocyte DNA from a case-control study of lung cancer involving minority populations. Mol. Carcinog 2000, 27, 34–46. [Google Scholar]
  60. Cheng, YW; Chen, CY; Lin, P; Huang, KH; Lin, TS; Wu, MH; Lee, H. DNA adduct level in lung tissue may act as a risk biomarker of lung cancer. Eur. J. Cancer 2000, 36, 1381–1388. [Google Scholar]
  61. Popp, W; Schell, C; Kraus, R; Vahrenholz, C; Wolf, R; Radtke, J; Bierwirth, K; Norpoth, K. DNA strand breakage and DNA adducts in lymphocytes of oral cancer patients. Carcinogenesis 1993, 14, 2251–2256. [Google Scholar]
  62. Peluso, M; Airoldi, L; Magagnotti, C; Fiorini, L; Munnia, A; Hautefeuille, A; Malaveille, C; Vineis, P. White blood cell DNA adducts and fruit and vegetable consumption in bladder cancer. Carcinogenesis 2000, 21, 183–187. [Google Scholar]
  63. Rothman, K. Modern Epidemiology; Little Brown & Co: Boston, MA, USA, 1986. [Google Scholar]
  64. Benhamou, S; Laplanche, A; Guillonneau, B; Mejean, A; Desgrandchamps, F; Schrameck, C; Degieux, V; Perin, F. DNA adducts in normal bladder tissue and bladder cancer risk. Mutagenesis 2003, 18, 445–448. [Google Scholar]
  65. Peluso, M; Munnia, A; Hoek, G; Krzyzanowski, M; Veglia, F; Airoldi, L; Autrup, H; Dunning, A; Garte, S; Hainaut, P; Malaveille, C; Gormally, E; Matullo, G; Overvad, K; Raaschou-Nielsen, O; Clavel-Chapelon, F; Linseisen, J; Boeing, H; Trichopoulou, A; Trichopoulos, D; Kaladidi, A; Palli, D; Krogh, V; Tumino, R; Panico, S; Bueno-De-Mesquita, HB; Peeters, PH; Kumle, M; Gonzalez, CA; Martinez, C; Dorronsoro, M; Barricarte, A; Navarro, C; Quiros, JR; Berglund, G; Janzon, L; Jarvholm, B; Day, NE; Key, TJ; Saracci, R; Kaaks, R; Riboli, E; Vineis, P. DNA adducts and lung cancer risk: a prospective study. Cancer Res 2005, 65, 8042–8048. [Google Scholar]
  66. Bak, H; Autrup, H; Thomsen, BL; Tjønneland, A; Overvad, K; Vogel, U; Raaschou-Nielsen, O; Loft, S. Bulky DNA adducts as risk indicator of lung cancer in a Danish case-cohort study. Int. J. Cancer 2006, 118, 1618–1622. [Google Scholar]
  67. Schwartz, AG; Prysak, GM; Bock, CH; Cote, ML. The molecular epidemiology of lung cancer. Carcinogenesis 2007, 28, 507–518. [Google Scholar]
  68. Ryberg, D; Skaug, V; Hewer, A; Phillips, DH; Harries, LW; Wolf, CR; Ogreid, D; Ulvik, A; Vu, P; Haugen, A. Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk. Carcinogenesis 1997, 18, 1285–1289. [Google Scholar]
  69. Rojas, M; Alexandrov, K; Cascorbi, I; Brockmöller, J; Likhachev, A; Pozharisski, K; Bouvier, G; Auburtin, G; Mayer, L; Kopp-Schneider, A; Roots, I; Bartsch, H. High benzo[a]pyrene diol-epoxide DNA adduct levels in lung and blood cells from individuals with combined CYP1A1 MspI/Msp-GSTM1*0/*0 genotypes. Pharmacogenetics 1998, 8, 109–118. [Google Scholar]
  70. Schoket, B; Phillips, DH; Kostic, S; Vincze, I. Smoking-associated bulky DNA adducts in bronchial tissue related to CYP1A1 MspI and GSTM1 genotypes in lung patients. Carcinogenesis 1998, 19, 841–846. [Google Scholar]
  71. Li, D; Firozi, PF; Zhang, W; Shen, J; DiGiovanni, J; Lau, S; Evans, D; Friess, H; Hassan, M; Abbruzzese, JL. DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. Mutat. Res 2002, 513, 37–48. [Google Scholar]
Table
Table 1A. Relationship between smoking and carcinogenic-DNA adducts in target organs due to tobacco smoke.
Table 1A. Relationship between smoking and carcinogenic-DNA adducts in target organs due to tobacco smoke.
Source of DNAMethodsHigher DNA adducts in smokers than ex-and non-smokers
Lung [18]32P-postlabeling29 cancer cases (17 smokers, 7 ex-smokers, 5 non-smokers)
Bladder [19]32P-postlabeling39 healthy subjects (18 smokers, 21 non-smokers)
Lung [20]HPLC/fluorescence, 32P-postlabeling13 cancer cases (11 smokers, 2 ex-smokers)
Uterine cervix [21]32P-postlabeling16 HPV (10 smokers, 6 non-smoker)
Lung [22]32P-postlabeling, fluorescence39 cancer cases (26 smokers, 11 ex-smokers, 2 non-smokers)
Pancreas [23]32P-postlabeling20 cancer cases (10 smokers, 10 non-smokers)
24 controls
Lung [24]HPLC/fluorescence39 (12 smokers, 6 ex-smokers, 21 non-smokers)
Lung [25]HPLC/ECD detection of 8-oxo-dG30 healthy subjects (14 smokers, 7 ex-smokers, 9 non-smokers)
Table
Table 1B. Relationship between smoking and carcinogenic-DNA adducts in cancer-target organs due to tobacco smoke and influence of metabolic genotypes.
Table 1B. Relationship between smoking and carcinogenic-DNA adducts in cancer-target organs due to tobacco smoke and influence of metabolic genotypes.
Source of DNAMethodsElevated DNA adducts in smokers than non-smokers
Lung [40]32P-postlabelingHigh adduct levels associated with CYP1A1 among subjects with GSTM1 null
Lung [41]32P-postlabelingHigh adducts in individuals with GSTM1 null, GSTT1 null or GSTP1 wt
Lung [42]32P-postlabelingIn smokers increased adduct levels in both nasal mucosa and lymphocytes. No significant effect of CYP1A1, GSTM1 and GSTT1
Lymphocytes [43]32P-postlabelingIn smokers with CYP1A1 MspI allele variant. Adduct levels no influenced by GST genotypes
Mononuclear cells [44]32P-postlabelingIn smokers with GSTM1 null (adjusted for the amount of cigarettes smoked per day) and in slow acetylators for both NAT1 and NAT2 with GSTM1 null than fast acetylator with GSTM1 (+)
Leukocytes [45]HPLC/fluorescenceIn smokers with high risk genotype (CYP1A1 allele variant, GSTM1 null, and GSTP1 wt)
BAL fluid and cells [46]32P-postlabelingIn smokers with MPO wt than MPO mutant genotype. The effect is gene dose-dependent
Lymphocytes [47]32P-postlabelingIn smokers with GSTM1 null, mEH*2 and GPX1*1
Lung [48]32P-postlabelingIn individuals with high CYP1A1 expression, but irrespective of the smoking status
Table
Table 2A. Relationship between smoking-related DNA adducts in tissues of cancer cases and/or controls.
Table 2A. Relationship between smoking-related DNA adducts in tissues of cancer cases and/or controls.
CancerMethodsRelationship
Lung [57]PAH-DNA adducts (white blood cells)
ELISA		Strong OR= 7.7 (1.7–34)
Lung [58]Bulky DNA adducts (lymphocytes)
32P-postlabeling		None
Lung [59]Bulky DNA adducts (lymphocytes)
32P-postlabeling		Present
Lung [60]Bulky DNA adducts (lung tissue)
32P-postlabeling		Strong OR= 25.19 (2.99–211.99)
Lung [27]Bulky DNA adducts (white blood cells)
32P-postlabeling		OR= 2.98 (1.05–8.42)
Oral [61]Bulky DNA adducts (white blood cells)
32P-postlabeling		None
Bladder [62]Bulky DNA adducts ((white blood cells)
32P-postlabeling		Strong OR= 5.25 (2.21–12.43)
Bladder [64]Bulky DNA adducts (bladder tissue)
32P-postlabeling		None
Lung, upper respiratory, bladder and leukemia [65]Bulky DNA adducts (white blood cells)
32P-postlabeling		None
Lung [66]Bulky DNA adducts (white blood cells)
32P-postlabeling		Present
Table
Table 2B. Relationship between smoking-related DNA adducts in tissues of cancer cases and/or controls and effect of metabolic polymorphisms.
Table 2B. Relationship between smoking-related DNA adducts in tissues of cancer cases and/or controls and effect of metabolic polymorphisms.
TissueMethodsNumber of subjectsElevated DNA adducts and metabolic polymorphism influence
Lung [68]32P-postlabeling70 cancer cases (smokers)In patients with GSTM1 null or GSTP1 wt than those with GSTM1 positive or GSTP1 polymorphic (n=70)
Lung [69]HPLC/fluorescence20 cancer cases (smokers)In patients (n=20) with GSTM1 null than those with GSTM1 (+)
Bronchus [70]32P-postlabeling124 cancer cases (70 smokers, 40 ex-smokers non-smokers 14)
26 controls (12 smokers, 5 ex-smokers, 9 non-smokers)		In cancer case than in controls. Adducts levels were not influenced by CYP1A1 or GSTM1 polymorphism
Lung [60]32P-postlabeling73 cancer cases (32 smokers, 38 non-smokers)
33 controls (11 smokers, 22 smokers)		In cancer cases than in controls, but not higher in smokers than non-smokers. Adducts not influenced by CYP1A1Msp1 or GSTM1 genotypes
Pancreas [71]32P-postlabeling and HPLC/ECD detection of 8-oxo-dG31 cancer cases
11 controls		In cancer cases than in controls. Association of DNA adducts with CYP1A1 polymorphism

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Lodovici, M.; Bigagli, E. Biomarkers of Induced Active and Passive Smoking Damage. Int. J. Environ. Res. Public Health 2009, 6, 874-888. https://doi.org/10.3390/ijerph6030874

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Lodovici M, Bigagli E. Biomarkers of Induced Active and Passive Smoking Damage. International Journal of Environmental Research and Public Health. 2009; 6(3):874-888. https://doi.org/10.3390/ijerph6030874

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Lodovici, Maura, and Elisabetta Bigagli. 2009. "Biomarkers of Induced Active and Passive Smoking Damage" International Journal of Environmental Research and Public Health 6, no. 3: 874-888. https://doi.org/10.3390/ijerph6030874

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