Tobacco products cause a variety of cancers, including those of the lung, oral cavity, nasal cavity, larynx, oropharynx, hypopharynx, oesophagus, stomach, liver, pancreas, bladder, ureter, kidney and cervix, and myeloid leukaemia. The carcinogens contained in tobacco products are responsible for these cancers.
There are more than 60 carcinogens in cigarette smoke and at least 16 in unburned tobacco. Among these, tobacco-specific nitrosamines (such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN)), polycyclic aromatic hydrocarbons (such as benzo[a]pyrene) and aromatic amines (such as 4-aminobiphenyl) seem to have an important role as causes of cancer.
Carcinogen biomarkers — DNA adducts, protein adducts and urinary metabolites — provide objective measures of carcinogen uptake and metabolic activation and detoxification in people who use, or are otherwise exposed to, tobacco products.
DNA adducts are central to the carcinogenic process as induced by tobacco products.
Among carcinogen biomarkers, DNA adducts potentially provide the most direct link to cancer, but there are still significant measurement problems. Protein adducts are useful alternatives to DNA adducts, and in some cases have provided significant mechanistic insights. Urinary metabolites are probably the most practical biomarkers and provide important information about carcinogen dose and metabolism.
Carcinogen biomarkers are important in establishing carcinogen dose in people who are exposed to tobacco products and in understanding mechanisms of carcinogenesis, and might ultimately be useful in predicting cancer risk.
The devastating link between tobacco products and human cancers results from a powerful alliance of two factors — nicotine and carcinogens. Without either one of these, tobacco would be just another commodity, instead of being the single greatest cause of death due to preventable cancer. Nicotine is addictive and toxic, but it is not carcinogenic. This addiction, however, causes people to use tobacco products continually, and these products contain many carcinogens. What are the mechanisms by which this deadly combination leads to 30% of cancer-related deaths in developed countries, and how can carcinogen biomarkers help to reveal these mechanisms?
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Mackay, J. & Eriksen, M. The Tobacco Atlas (World Health Organization, Geneva, 2002).
World Health Organization. The World Health Report 2002: Reducing Risks, Promoting Healthy Life (World Health Organization, Geneva, 2002).
International Agency for Research on Cancer. Tobacco smoke and involuntary smoking. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 83 (IARC, Lyon, in the press).
International Agency for Research on Cancer. Tobacco habits other than smoking: betel quid and Areca nut chewing and some related nitrosamines. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 37, 37–202 (IARC, Lyon, 1985).
International Agency for Research on Cancer. Tobacco Smoking. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 38, 37–375 (IARC, Lyon, 1986).
Hoffmann, D., Hoffmann, I. & El Bayoumy, K. The less harmful cigarette: a controversial issue. A tribute to Ernst L. Wynder. Chem. Res. Toxicol. 14, 767–790 (2001).
Hoffmann, D., Adams, J. D., Lisk, D., Fisenne, I. & Brunnemann, K. D. Toxic and carcinogenic agents in dry and moist snuff. J. Natl Cancer Inst. 79, 1281–1286 (1987).
Hoffmann, D. et al. Five leading US commercial brands of moist snuff in 1994: assessment of carcinogenic N-nitrosamines. J. Natl Cancer Inst. 87, 1862–1869 (1995).
Hecht, S. S. in Environmental and Occupational Medicine (ed. Rom, W. N.) 1479–1499 (Lippincott–Raven, New York, 1998).
Swauger, J. E., Steichen, T. J., Murphy, P. A. & Kinsler, S. An analysis of the mainstream smoke chemistry of samples of the US cigarette market acquired between 1995 and 2000. Regul. Toxicol. Pharmacol. 35, 142–156 (2002).
British Columbia Ministry of Health Planning. What is in Cigarettes? [online], (cited 4 Sept 2003), <http://www.healthplanning.gov.bc.ca/ttdr/index.html>.
Phillips, D. H. Fifty years of benzo[a]pyrene. Nature 303, 468–472 (1983).
Cooper, R. L., Lindsey, A. J. & Waller, R. E. The presence of 3,4–benzopyrene in cigarette smoke. Chem. Ind. 46, 1418 (1954).
Denissenko, M. F., Pao, A., Tang, M. & Pfeifer, G. P. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hot spots in p53. Science 274, 430–432 (1996). Proposes a role for benzo[ a ]pyrene-7,8-diol-9,10-epoxide–DNA adducts as causes of mutations found in the TP53 gene in lung cancer.
Pfeifer, G. P. et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21, 7435–7451 (2002).
Ross, J. A. et al. Adenomas induced by polycyclic aromatic hydrocarbons in strain A/J mouse lung correlate with time-integrated DNA adduct levels. Cancer Res. 55, 1039–1044 (1995).
Hoffmann, D., Schmeltz, I., Hecht, S. S. & Wynder, E. L. in Polycyclic Hydrocarbons and Cancer (eds Gelboin, H. & Ts'o, P. O. P.) 85–117 (Academic, New York, 1978).
Hecht, S. S. & Hoffmann, D. Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 9, 875–884 (1988).
Spiegelhalder, B. & Bartsch, H. Tobacco-specific nitrosamines. Eur. J. Cancer Prev. 5, 33–38 (1996).
Hoffmann, D., Brunnemann, K. D., Prokopczyk, B. & Djordjevic, M. V. Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines: chemistry, biochemistry, carcinogenicity, and relevance to humans. J. Toxicol. Environ. Health 41, 1–52 (1994).
Vainio, H. & Weiderpass, E. Smokeless tobacco: harm reduction or nicotine overload? Eur. J. Cancer Prev. 12, 89–92 (2003).
Hecht, S. S. Tobacco smoke carcinogens and lung cancer. J. Natl Cancer Inst. 91, 1194–1210 (1999).
International Agency for Research on Cancer. Polynuclear aromatic compounds, part 1: chemical, environmental, and experimental data. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 32, 33–91 (IARC, Lyon, 1983).
Deutsch-Wenzel, R., Brune, H. & Grimmer, G. Experimental studies in rat lungs on the carcinogenicity and dose-response relationships of eight frequently occurring environmental polycyclic aromatic hydrocarbons. J. Natl Cancer Inst. 71, 539–544 (1983).
Boysen, G. & Hecht, S. S. Analysis of DNA and protein adducts of benzo[a]pyrene in human tissues using structure-specific methods. Mutation Res. 543, 17–30 (2003).
Phillips, D. H. Smoking-related DNA and protein adducts in human tissues. Carcinogenesis 23, 1979–2004 (2002). Provides a comprehensive review of DNA and protein adducts of cigarette-smoke carcinogens in human tissues.
Hecht, S. S. Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem. Res. Toxicol. 11, 559–603 (1998).
Belinsky, S. A., Foley, J. F., White, C. M., Anderson, M. W. & Maronpot, R. R. Dose-response relationship between O6-methylguanine formation in Clara cells and induction of pulmonary neoplasia in the rat by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res. 50, 3772–3780 (1990). Shows a relationship between lung-tumour induction by NNK and O6-methylguanine adducts in rats.
Schlöbe, D., Hölze, D., Richter, E. & Tricker, A. R. Determination of tobacco-specific nitrosamine hemoglobin and lung DNA adducts. Proc. Am. Assoc. Cancer Res. 43, 346 (2002).
Hecht, S. S. Human urinary carcinogen metabolites: biomarkers for investigating tobacco and cancer. Carcinogenesis 23, 907–922 (2002). Provides a comprehensive review of urinary metabolites and related compounds as tobacco-carcinogen biomarkers.
Shapiro, J. A., Jacobs, E. J. & Thun, M. J. Cigar smoking in men and risk of death from tobacco-related cancers. J. Natl Cancer Inst. 92, 333–337 (2000).
Boffetta, P. et al. Cigar and pipe smoking and lung cancer risk: a multicenter study from Europe. J. Natl Cancer Inst. 91, 697–701 (1999).
Travis, W. D., Travis, L. B. & Devesa, S. S. Lung cancer. Cancer 75, 191–202 (1995).
Preussmann, R. & Stewart, B. W. in Chemical Carcinogens 2nd edn (ed. Searle, C. E.) American Chemical Society Monograph 182 Vol. 2, 643–828 (ACS, Washington DC, 1984).
International Agency for Research on Cancer. Wood dust and formaldehyde. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 62, 217–362 (IARC, Lyon, 1995).
International Agency for Research on Cancer. Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide (part two). IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 71, 319–335 (IARC, Lyon, 1999).
Hoffmann, D. & Hecht, S. S. in Handbook of Experimental Pharmacology (eds Cooper, C. S. & Grover, P. L.) 63–102 (Springer–Verlag, Heidelberg, 1990).
Hecht, S. S. et al. Induction of oral cavity tumors in F344 rats by tobacco-specific nitrosamines and snuff. Cancer Res. 46, 4162–4166 (1986). Shows that a mixture of NNN and NNK induces oral tumours in rats and that oral tumours can also be induced by snuff.
Lijinsky, W. Chemistry and Biology of N-Nitroso Compounds (Cambridge Univ. Press, Cambridge, England, 1992).
Hecht, S. S. & Hoffmann, D. The relevance of tobacco-specific nitrosamines to human cancer. Cancer Surv. 8, 273–294 (1989).
International Agency for Research on Cancer. Dry cleaning, some chlorinated solvents and other industrial chemicals. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 63, 393–407 (IARC, Lyon, France, 1995).
Rivenson, A., Hoffmann, D., Prokopczyk, B., Amin, S. & Hecht, S. S. Induction of lung and exocrine pancreas tumors in F344 rats by tobacco-specific and Areca-derived N-nitrosamines. Cancer Res. 48, 6912–6917 (1988). Shows that NNK induces tumours of the lung and pancreas when administered in drinking water to rats.
Prokopczyk, B. et al. Identification of tobacco-derived compounds in human pancreatic juice. Chem. Res. Toxicol. 15, 677–685 (2002).
Prokopczyk, B., Trushin, N., Leszczynska, J., Waggoner, S. E. & El Bayoumy, K. Human cervical tissue metabolizes the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, via α-hydroxylation and carbonyl reduction pathways. Carcinogenesis 22, 107–114 (2001).
Melikian, A. A. et al. Identification of benzo[a]pyrene metabolites in cervical mucus and DNA adducts in cervical tissues in humans by gas chromatography-mass spectrometry. Cancer Lett. 146, 127–134 (1999).
International Agency for Research on Cancer. Human papillomaviruses. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 64, 35–378 (IARC, Lyon, 1995).
International Agency for Research on Cancer. Some aromatic amines, hydrazine and related substances, N-nitroso compounds and miscellaneous alkylating agents. IARC Monographs on the Carcinogenic Risk of Chemicals to Man Vol. 4, 97–111 (IARC, Lyon, FR, 1973).
Skipper, P. L. & Tannenbaum, S. R. Protein adducts in the molecular dosimetry of chemical carcinogens. Carcinogenesis 11, 507–518 (1990).
Skipper, P. L., Peng, X., SooHoo, C. K. & Tannenbaum, S. R. Protein adducts as biomarkers of human carcinogen exposure. Drug Metab. Rev. 26, 111–124 (1994).
Landi, M. T. et al. Cytochrome P4501A2: enzyme induction and genetic control in determining 4-aminobiphenyl-hemoglobin adduct levels. Cancer Epidemiol. Biomarkers Prev. 5, 693–698 (1996).
Probst-Hensch, N. M. et al. N-Acetyltransferase 2 phenotype but not NAT1*10 genotype affects aminobiphenyl–hemoglobin adduct levels. Cancer Epidemiol. Biomarkers Prev. 9, 619–623 (2000).
Castelao, J. E. et al. Gender- and smoking-related bladder cancer risk. J. Natl Cancer Inst. 93, 538–545 (2001).
International Agency for Research on Cancer. Some industrial chemicals and dyestuffs. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 29, 93–148 (IARC, Lyon, 1982).
Pryor, W. A., Stone, K., Zang, L. Y. & Bermudez, E. Fractionation of aqueous cigarette tar extracts: fractions that contain the tar radical cause DNA damage. Chem. Res. Toxicol. 11, 441–448 (1998).
Guengerich, F. P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol. 14, 611–650 (2001).
Cooper, C. S., Grover, P. L. & Sims, P. The metabolism and activation of benzo[a]pyrene. Prog. Drug Metab. 7, 295–396 (1983).
Wu, K. Y. et al. A gas chromatography/electron capture/negative chemical ionization high-resolution mass spectrometry method for analysis of endogenous and exogenous N7-(2-hydroxyethyl)guanine in rodents and its potential for human biological monitoring. Chem. Res. Toxicol. 12, 722–729 (1999).
Talaska, G. et al. Detection of carcinogen–DNA adducts in exfoliated urothelial cells of cigarette smokers: association with smoking, hemoglobin adducts, and urinary mutagenicity. Cancer Epidemiol. Biomarkers Prev. 1, 61–66 (1991).
Poirier, M. C. & Weston, A. in Encyclopedia of Cancer Vol. 2. (ed. Bernito, J. R.) 79–87 (Academic, London, 2002).
Wei, Q. et al. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J. Natl Cancer Inst. 92, 1764–1772 (2000).
Norbury, C. J. & Hickson, I. D. Cellular responses to DNA damage. Ann. Rev. Pharmacol. Toxicol. 41, 367–401 (2001).
Goode, E. L., Ulrich, C. M. & Potter, J. D. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol. Biomarkers Prev. 11, 1513–1530 (2002).
Loechler, E. L., Green, C. L. & Essigmann, J. M. In vivo mutagenesis by O6-methylguanine built into a unique site in a viral genome. Proc. Natl Acad. Sci. USA 81, 6271–6275 (1984). Shows that O6-methylguanine specifically causes G to A mutations during cell replication.
Singer, B. & Essigmann, J. M. Site-specific mutagenesis: retrospective and prospective. Carcinogenesis 12, 949–955 (1991).
Seo, K. Y., Jelinsky, S. A. & Loechler, E. L. Factors that influence the mutagenic patterns of DNA adducts from chemical carcinogens. Mutat. Res. 463, 215–246 (2000).
Osada, H. & Takahashi, T. Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer. Oncogene 21, 7421–7434 (2002).
Boysen, G., Kenney, P. M. J., Upadhyaya, P., Wang, M. & Hecht, S. S. Effects of benzyl isothiocyanate and 2-phenethyl isothiocyanate on benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism in F-344 rats. Carcinogenesis 24, 517–525 (2003).
Kensler, T. W., Groopman, J. D., Sutter, T. R., Curphey, T. J. & Roebuck, B. D. Development of cancer chemopreventive agents: Oltipraz as a paradigm. Chem. Res. Toxicol. 12, 113–126 (1999).
Adriaenssens, P. I., White, C. M. & Anderson, M. W. Dose-response relationships for the binding of benzo[a]pyrene metabolites to DNA and protein in lung, liver, and forestomach of control and butylated hydroxyanisole-treated mice. Cancer Res. 43, 3712–3719 (1983).
Miller, J. A. Research in chemical carcinogenesis with Elizabeth Miller — a trail of discovery with our associates. Drug Metabol. Dispos. 26, 1–36 (1994).
Schuller, H. M. Mechanisms of smoking-related lung and pancreatic adenocarcinoma development. Nature Rev. Cancer 2, 455–463 (2002).
West, K. A. et al. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J. Clin. Invest. 111, 81–90 (2003).
Heeschen, C. et al. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nature Med. 7, 833–839 (2001).
Habs, M. & Schmahl, D. Influence of five different postnatal lifelong treatments on the transplacental carcinogenicity of ethylnitrosourea in Sprague–Dawley rats. Cancer Lett. 2, 93–100 (1976).
Gurkalo, V. K. & Volfson, N. I. Nicotine influence upon the development of experimental stomach tumors. Arch. Geschwulstforsch. 52, 259–265 (1982).
Bock, F. G. in Banbury Report 3: A Safe Cigarette? (eds Gori, G. B. & Bock, F. G.) 129–139 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1980).
Berger, M. R., Petru, E., Habs, M. & Schmahl, D. Influence of perinatal nicotine administration on transplacental carcinogenesis in Sprague–Dawley rats by N-methylnitrosourea. Br. J. Cancer 55, 37–40 (1987).
Chen, Y. P. & Squier, C. A. Effect of nicotine on 7,12-dimethylbenz[a]anthracene carcinogenesis in hamster cheek pouch. J. Natl Cancer Inst. 82, 861–864 (1990).
Chen, Y. P., Johnson, G. K. & Squier, C. A. Effects of nicotine and tobacco-specific nitrosamines on hamster cheek pouch and gastric mucosa. J. Oral Pathol. Med. 23, 251–255 (1994).
US Department of Health and Human Services Survey of Compounds Which Have Been Tested for Carcinogenic Activity (GMA Industries, Inc., Annapolis, 2003).
Schuller, H. M., McGavin, M. D., Orloff, M., Riechert, A. & Porter, B. Simultaneous exposure to nicotine and hyperoxia causes tumors in hamsters. Lab. Invest. 73, 448–456 (1995).
Hecht, S. S., Carmella, S., Mori, H. & Hoffmann, D. Role of catechol as a major cocarcinogen in the weakly acidic fraction of smoke condensate. J. Natl Cancer Inst. 66, 163–169 (1981).
Van Duuren, B. L., Katz, C. & Goldschmidt, B. M. Brief communication: cocarcinogenic agents in tobacco carcinogenesis. J. Natl Cancer Inst. 51, 703–705 (1973).
Hoffmann, D. & Wynder, E. L. A study of tobacco carcinogenesis. XI. Tumor initiators, tumor accelerators, and tumor promoting activity of condensate fractions. Cancer 27, 848–864 (1971). Identifies the principal mouse-skin carcinogenic, co-carcinogenic and tumour-promoting fractions of cigarette-smoke condensate.
Dong, Z., Birrer, M. J., Watts, R. G., Matrisian, L. M. & Colburn, N. H. Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc. Natl Acad. Sci. USA 91, 609–613 (1994).
Fischer, S. M. in Comprehensive Toxicology, Vol. 12, Chemical Carcinogens and Anticarcinogens (eds Bowden, G. T. & Fischer, S. M.) 349–381 (Elsevier Science, New York, 1997).
Baylin, S. B., Herman, J. G., Graff, J. R., Vertino, P. M. & Issa, J. P. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv. Cancer Res. 72, 141–196 (1998).
Palmisano, W. A. et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res. 60, 5954–5958 (2000).
Hecht, S. S. Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet Oncol. 3, 461–469 (2002).
Park, I. W. et al. Multiple clonal abnormalities in the bronchial epithelium of patients with lung cancer. J. Natl Cancer Inst. 91, 1863–1868 (1999).
Wistuba, I. I., Mao, L. & Gazdar, A. F. Smoking molecular damage in bronchial epithelium. Oncogene 21, 7298–7306 (2002).
Harris, C. C. et al. Interindividual variation in binding of benzo[a]pyrene to DNA in cultured human bronchi. Science 194, 1067–1069 (1976). Shows large inter-individual differences in the ability to metabolically activate benzo[ a ]pyrene to DNA adducts.
World Health Organization World Cancer Report (eds Stewart, B. W. & Kleihues, P.) (IARC, Lyon, 2003).
Bach, P. B. et al. Variations in lung cancer risk among smokers. J. Natl Cancer Inst. 95, 470–478 (2003).
Kriek, E., Rojas, M., Alexandrov, K. & Bartsch, H. Polycyclic aromatic hydrocarbon–DNA adducts in humans: relevance as biomarkers for exposure and cancer risk. Mutat. Res. 400, 215–231 (1998).
Wiencke, J. K. DNA adduct burden and tobacco carcinogenesis. Oncogene 21, 7376–7391 (2002).
Phillips, D. H. et al. Methods of DNA adduct determination and their application to testing compounds for genotoxicity. Environ. Mol. Mutagen. 35, 222–233 (2000).
Gammon, M. D. et al. Environmental toxins and breast cancer on Long Island. I. Polycyclic aromatic hydrocarbon DNA adducts. Cancer Epidemiol. Biomarkers Prev. 11, 677–685 (2002).
Veglia, F., Matullo, G. & Vineis, P. Bulky DNA adducts and risk of cancer: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 12, 157–160 (2003).
Tang, D. et al. Association between carcinogen–DNA adducts in white blood cells and lung cancer risk in the physicians health study. Cancer Res. 61, 6708–6712 (2001).
Hecht, S. S. & Tricker, A. R. in Analytical Determination of Nicotine and Related Compounds and Their Metabolites (eds Gorrod, J. W. & Jacob, P.) 421–488 (Elsevier Science, Amsterdam, 1999).
Foiles, P. G. et al. Mass spectrometric analysis of tobacco-specific nitrosamine–DNA adducts in smokers and nonsmokers. Chem. Res. Toxicol. 4, 364–368 (1991).
Tyroller, S., Zwickenpflug, W. & Richter, E. New sources of dietary myosmine uptake from cereals, fruits, vegetables, and milk. J. Agric. Food Chem. 50, 4909–4915 (2002).
Wilp, J., Zwickenpflug, W. & Richter, E. Nitrosation of dietary myosmine as risk factor of human cancer. Food Chem. Toxicol. 40, 1223–1228 (2002).
Osterman-Golkar, S., Ehrenberg, L., Segerback, D. & Hallstrom, I. Evaluation of genetic risks of alkyating agents II. Haemoglobin as a dose monitor. Mutat. Res. 34, 1–10 (1976).
Ehrenberg, L. & Osterman-Golkar, S. Alkylation of macromolecules for detecting mutagenic agents. Teratogenesis Carcinog. Mutagen. 1, 105–127 (1980).
Mowrer, J., Tornqvist, M., Jensen, S. & Ehrenberg, L. Modified Edman degradation applied to hemoglobin for monitoring occupational exposure to alkylating agents. Toxicol. Environ. Chem. 11, 215–231 (1986).
Tornqvist, M. & Ehrenberg, L. Estimation of cancer risk caused by environmental chemicals based on in vivo dose measurement. J. Environ. Pathol. Toxicol. Oncol. 20, 263–271 (2001).
Bergmark, E. Hemoglobin adducts of acrylamide and acrylonitrile in laboratory workers, smokers and nonsmokers. Chem. Res. Toxicol. 10, 78–84 (1997).
Fennell, T. R. et al. Hemoglobin adducts from acrylonitrile and ethylene oxide in cigarette smokers: effects of glutathione-S-transferase T1-null and M1-null genotypes. Cancer Epidemiol. Biomarkers Prev. 9, 705–712 (2000).
Carmella, S. G. et al. Ethylation and methylation of hemoglobin in smokers and non-smokers. Carcinogenesis 23, 1903–1910 (2002).
Kopplin, A., Eberle-Adamkiewicz, G., Glusenkmo, K. H., Nehls, P. & Kirstein, U. Urinary excretion of 3-methyladenine and 3-ethyladenine after controlled exposure to tobacco smoke. Carcinogenesis 16, 2637–2641 (1995).
Prevost, V. & Shuker, D. E. G. Cigarette smoking and urinary 3-alkyladenine excretion in man. Chem. Res. Toxicol. 9, 439–444 (1996).
Godschalk, R. et al. Comparison of multiple DNA adduct types in tumor adjacent human lung tissue: effect of cigarette smoking. Carcinogenesis 23, 2081–2086 (2002).
Carmella, S. G., Akerkar, S. & Hecht, S. S. Metabolites of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers' urine. Cancer Res. 53, 721–724 (1993).
Carmella, S. G., Akerkar, S., Richie, J. P. Jr & Hecht, S. S. Intraindividual and interindividual differences in metabolites of the tobacco-specific lung carcinogen 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) in smokers' urine. Cancer Epidemiol. Biomarkers Prev. 4, 635–642 (1995).
Kresty, L. A. et al. Metabolites of a tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the urine of smokeless tobacco users: relationship of urinary biomarkers and oral leukoplakia. Cancer Epidemiol. Biomarkers Prev. 5, 521–525 (1996).
Richie, J. P. et al. Differences in the urinary metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in black and white smokers. Cancer Epidemiol. Biomarkers Prev. 6, 783–790 (1997).
Hecht, S. S. et al. Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers. Cancer Epidemiol. Biomarkers Prev. 4, 877–884 (1995).
Taioli, E. et al. Effects of indole-3-carbinol on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokers. Cancer Epidemiol. Biomarkers Prev. 6, 517–522 (1997).
Hecht, S. S. et al. Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation. Cancer Res. 59, 590–596 (1999).
Hecht, S. S. et al. Quantitation of metabolites of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone after cessation of smokeless tobacco use. Cancer Res. 62, 129–134 (2002).
Hecht, S. S. et al. Effects of reduced cigarette smoking on uptake of a tobacco-specific lung carcinogen. J. Natl Cancer Inst. (in the press).
Hecht, S. S. et al. A tobacco-specific lung carcinogen in the urine of men exposed to cigarette smoke. N. Engl. J. Med. 329, 1543–1546 (1993).
Parsons, W. D., Carmella, S. G., Akerkar, S., Bonilla, L. E. & Hecht, S. S. A metabolite of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the urine of hospital workers exposed to environmental tobacco smoke. Cancer Epidemiol. Biomarkers Prev. 7, 257–260 (1998).
Anderson, K. E. et al. Metabolites of a tobacco-specific lung carcinogen in the urine of nonsmoking women exposed to environmental tobacco smoke in their homes. J. Natl Cancer Inst. 93, 378–381 (2001). Establishes the presence of NNAL and NNAL-Glucs in the urine of non-smoking women exposed to environmental tobacco smoke at home, and relates the amounts of these to those in their smoking spouses.
Hecht, S. S. et al. Metabolites of a tobacco-specific lung carcinogen in the urine of elementary school-aged children. Cancer Epidemiol. Biomarkers Prev. 10, 1109–1116 (2001).
Lackmann, G. M. et al. Metabolites of a tobacco-specific carcinogen in the urine of newborns. J. Natl Cancer Inst. 91, 459–465 (1999).
Milunsky, A., Carmella, S. G., Ye, M. & Hecht, S. S. A tobacco-specific carcinogen in the fetus. Prenat. Diagn. 20, 307–310 (2000).
Morrow, J. D. et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. N. Engl. J. Med. 332, 1198–1203 (1995).
Nia, A. B. et al. Immunoperoxidase detection of polycyclic aromatic hydrocarbon–DNA adducts in mouth floor and buccal mucosa cells of smokers and nonsmokers. Environ. Mol. Mutagen. 36, 127–133 (2000).
Nia, A. B. et al. Applicability of induced sputum for molecular dosimetry of exposure to inhalatory carcinogens: 32P-postlabeling of lipophilic DNA adducts in smokers and nonsmokers. Cancer Epidemiol. Biomarkers Prev. 9, 367–372 (2000).
Nia, A. B., Maas, L. M., Brouwer, E. M., Kleinjans, J. C. & van Schooten, F. J. Comparison between smoking-related DNA adduct analysis in induced sputum and peripheral blood lymphocytes. Carcinogenesis 21, 1335–1340 (2000).
Benhamou, S. et al. Meta- and pooled analyses of the effects of glutathione-S-transferase M1 polymorphisms and smoking on lung cancer risk. Carcinogenesis 23, 1343–1350 (2002).
Caporaso, N. E. Why have we failed to find the low penetrance genetic constituents of common cancers? Cancer Epidemiol. Biomarkers Prev. 11, 1544–1549 (2002).
Bartsch, H. et al. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol. Biomarkers Prev. 9, 3–28 (2000).
Houlston, R. S. CYP1A1 polymorphisms and lung cancer risk: a meta-analysis. Pharmacogenetics 10, 105–114 (2000).
Spivack, S. D., Fasco, M. J., Walker, V. E. & Kaminsky, L. S. The molecular epidemiology of lung cancer. Crit. Rev. Toxicol. 27, 319–365 (1997).
Simpson, C. D. et al. Determination of r-7,t-8,9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene in human urine by gas chromatography-negative ion chemical ionization-mass spectrometry. Chem. Res. Toxicol. 13, 271–280 (2000).
Thun, M. J., Henley, S. J. & Calle, E. E. Tobacco use and cancer: an epidemiologic perspective for geneticists. Oncogene 21, 7307–7325 (2002).
Skipper, P. L. & Stillwell, W. G. in Hemoglobins. Part B. Biochemical and Analytical Methods (eds Everse, J., Vandegriff, K. D. & Winslow, R. M.) 643–649 (Academic, San Diego, 1994).
Hecht, S. S., Carmella, S. G. & Murphy, S. E. Tobacco-specific nitrosamine hemoglobin adducts. Methods Enzymol. 231, 657–667 (1994).
Törnqvist, M. in Hemoglobins. Part B. Biochemical and Analytical Methods Vol. 231 (eds Everse, J., Vandegriff, K. D. & Winslow, R. M.) 650–657 (Academic, San Diego, 1994).
Hayes, R. B. et al. Mortality among benzene-exposed workers in China. Environ. Health Perspect. 104 (Suppl. 6), 1349–1352 (1996).
International Agency for Research on Cancer. Some industrial chemicals. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 60, 73–159 (IARC, Lyon, 1994).
Research in the Hecht laboratory is supported by grants from the US National Institutes of Health, the American Cancer Society and the Flight Attendant Medical Research Institute. I thank S. G. Carmella, who has contributed substantially to our biomarker research, and my other colleagues and collaborators who have been involved in our research. I appreciate the editorial assistance of R. Carlson.
- SMOKELESS TOBACCO PRODUCTS
Tobacco products that do not produce smoke, such as chewing tobacco and oral snuff.
- ENVIRONMENTAL TOBACCO SMOKE
The material in indoor air (usually) that results from tobacco smoking. It is produced mainly by the release of smoke from the burning tip of a cigarette between puffs and the smoke exhaled by the smoker. Environmental tobacco smoke is also known as secondhand smoke.
- CARCINOGEN BIOMARKERS
Quantifiable substances such as carcinogen–DNA adducts, carcinogen–protein adducts and urinary metabolites of carcinogens, which are derived from specific carcinogens.
- MAINSTREAM SMOKE
The smoke that is emitted at the mouth end of the cigarette during puffing.
- SIDESTREAM SMOKE
The smoke that is emitted from the burning cone between puffs, which comprises most environmental tobacco smoke.
- STRONG CARCINOGEN
A carcinogen that reproducibly produces tumours in laboratory animals after treatment with relatively low doses (typically micrograms or milligrams).
- WEAK CARCINOGEN
A carcinogen that produces tumours in laboratory animals only after administration of relatively high doses.
These increase the carcinogenic activity of carcinogens when administered simultaneously. Examples in cigarette smoke include catechol and methylcatechols.
- TUMOUR PROMOTERS
These enhance carcinogenic activity when administered after the carcinogen. The best known example is 12-O-tetradecanoyl-phorbol-13-acetate (TPA), although this is not present in tobacco products. Tumour promoters of tobacco products are mainly uncharacterized.
- DNA ADDUCT
A covalent binding product of a carcinogen or related substance or its metabolite to DNA.
- PARTICULATE PHASE
That portion of tobacco smoke that is retained on a glass-fibre filter.
- PROTEIN ADDUCT
A covalent binding product of a carcinogen or related substance, or its metabolite, to a protein.
A sensitive technique for detecting carcinogen–DNA adducts. DNA is hydrolysed enzymatically to nucleoside-3′-monophosphates, which are then labelled at the 5′-position with [γ-32P]ATP of high specific activity. The resulting labelled nucleoside diphosphates are then separated and detected.
- ETHYLATING AGENT
A compound that can add an ethyl group to another molecule, such as DNA or a protein.
- BAY REGION
The angular region, resembling a bay, of a polycyclic aromatic hydrocarbon molecule, such as the 4–5 positions of phenanthrene or the 10–12 positions of benzo[a]pyrene.
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Hecht, S. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3, 733–744 (2003). https://doi.org/10.1038/nrc1190
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