METABOLISM OF CARCINOGENIC TOBACCO SPECIFIC NITROSAMINES

Summary

Principal Investigator: Stephen Hecht
Abstract: Cigarette smoking causes approximately 30% of all cancer death in the U.S. It is responsible for 85% of the 160,000 lung cancer deaths expected in 1998. Snuff-dipping is an acknowledged cause of oral cavity cancer and the use of moist snuff in the U.S. has increased remarkably in recent years. In spite of advances in tobacco control and smoking cessation, there are still 48 million smokers in the U.S., about 25% of the adult population. Approximately 500 billion cigarettes and 121 million pounds of smokeless tobacco were consumed in 1997 in the U.S. Tobacco-specific N-nitrosamines are formed from tobacco alkaloids during the curing and processing of tobacco products. Two of these, 4- (methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) and N- nitrosonornicotine (NNN), are present in substantial quantities and are strong carcinogens. NNK is a potent pulmonary carcinogen in rodents and also induces tumors of the pancreas, nasal mucosa, and liver. NNN causes tumors of the esophagus and nasal mucosa in rats and respiratory tract tumors in mice and hamsters. A mixture of NNK and NNN induces oral tumors in rats. Based on their carcinogenic activities, the extensive data on the occurrence of NNK and NNN in tobacco products, and on biochemical studies, it is our hypothesis that these compounds play a significant role as causative factors in human cancers associated with tobacco use. Although there are parallels between NNK and NNN metabolism in rodents and humans which support our hypothesis, there are key aspects which must be explored to further evaluate our hypothesis. Therefore, our specific aims are: 1) investigate stereoselectivity on the metabolism of NNK and NNN by delineating differences in the formation and further metabolism of enantiomers of the major NNK metabolite NNAL, determining differences in the stereoselectivity of metabolic activation of NNK, and examining differences in the metabolic activation and carcinogenicity of NNN enantiomers; 2) investigate DNA and protein pyridyloxo-butylation by NNK and NNN by elucidating the structures of the major adducts formed with DNA and hemoglobin; and 3) investigate the metabolism of NNK and NNN in humans by determining levels of NNN metabolites in human urine, characterizing previously unknown NNN metabolites, and examining NNK metabolites in the urine of snuff-dippers to determine their persistence after cessation and their amounts as a function of dose. The overall theme of this proposal is mechanistic studies of NNK and NNN metabolism and adduct formation, in order to further evaluate the carcinogenic potential of NNK and NNN in humans exposed to tobacco products. We believe that an understanding of the mechanisms by which tobacco smoke carcinogens cause cancer will lead to new insights on individual cancer susceptibility and development of innovative strategies to prevent tobacco related cancers.
Funding Period: 1999-04-01 - 2004-01-31
more information: NIH RePORT

Top Publications

  1. pmc It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco
    Stephen S Hecht
    Author s Affiliation Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
    Cancer Prev Res (Phila) 7:639-47. 2014
  2. pmc Metabolites of a tobacco-specific lung carcinogen in children exposed to secondhand or thirdhand tobacco smoke in their homes
    Janet L Thomas
    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Cancer Epidemiol Biomarkers Prev 20:1213-21. 2011
  3. pmc The ratio of a urinary tobacco-specific lung carcinogen metabolite to cotinine is significantly higher in passive than in active smokers
    Rachel I Vogel
    Masonic Cancer Center, University of Minnesota, Minneapolis, USA
    Biomarkers 16:491-7. 2011
  4. pmc The sphingolipid degradation product trans-2-hexadecenal forms adducts with DNA
    Pramod Upadhyaya
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Biochem Biophys Res Commun 424:18-21. 2012
  5. pmc Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosonornicotine in humans
    Aleksandar Knezevich
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Nicotine Tob Res 15:591-5. 2013
  6. pmc Lung carcinogenesis by tobacco smoke
    Stephen S Hecht
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Int J Cancer 131:2724-32. 2012
  7. pmc Levels of (S)-N'-nitrosonornicotine in U.S. tobacco products
    Irina Stepanov
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Nicotine Tob Res 15:1305-10. 2013
  8. pmc Analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing DNA adducts in human exfoliated oral mucosa cells by liquid chromatography-electrospray ionization-tandem mass spectrometry
    Irina Stepanov
    Masonic Cancer Center and Division of Environmental Health Sciences, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, United States
    Chem Res Toxicol 26:37-45. 2013
  9. pmc (S)-N'-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats
    Silvia Balbo
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Carcinogenesis 34:2178-83. 2013
  10. pmc Tobacco-specific N-nitrosamine exposures and cancer risk in the Shanghai Cohort Study: remarkable coherence with rat tumor sites
    Irina Stepanov
    Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN Masonic Cancer Center, University of Minnesota, Minneapolis, MN
    Int J Cancer 134:2278-83. 2014

Scientific Experts

  • Irina Stepanov
  • Stephen Hecht
  • Pramod Upadhyaya
  • Peter W Villalta
  • Mingyao Wang
  • Yanbin Lao
  • Steven G Carmella
  • Silvia Balbo
  • Janet L Thomas
  • Bruce R Lindgren
  • Siyi Zhang
  • Guang Cheng
  • Fekadu Kassie
  • Sharon E Murphy
  • Jian Min Yuan
  • Xun Ming
  • Dipankar Bandyopadhyay
  • Lijiao Zhao
  • Samir S Khariwala
  • Aleksandar Knezevich
  • Shana J Sturla
  • Jasjit S Ahluwalia
  • Andrea Yoder
  • Dorothy K Hatsukami
  • Rachel I Vogel
  • Laura A Maertens
  • Li Li
  • Elizabeth A McNiel
  • Nanxiong Yu
  • Diana Porubin
  • John R Jalas
  • Hansen L Wong
  • Xianghua Luo
  • Lesley M Butler
  • Natalie Olvera
  • John Muzic
  • Sandra James-Yi
  • Charles S Johnson
  • Steven Carmella
  • Claire Brookmeyer
  • Michael G O'Sullivan
  • Ashok Kumar
  • Robert Bittman
  • Julie D Saba
  • Hoe Sup Byun
  • Shaomei Han
  • Hongfei Guo
  • Larry C An
  • Andrew Davis
  • Cheryl L Zimmerman
  • Aziz Sancar
  • Joyce T Reardon
  • Lisa A Peterson
  • Elizabeth V Wattenberg
  • Joana Perdigao
  • Anthony E Pegg
  • J Bradley Hochalter
  • Stephen Kalscheuer
  • Robin L Bliss
  • Lori A Heath
  • Zhong ze Li
  • Ky Anh Le
  • Maria Gonta
  • Edward J McIntee
  • Qing Yu Zhang
  • Xiuling Zhang
  • Jana Scott
  • Xinxin Ding
  • Jun Gu

Detail Information

Publications57

  1. pmc It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco
    Stephen S Hecht
    Author s Affiliation Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
    Cancer Prev Res (Phila) 7:639-47. 2014
    ....
  2. pmc Metabolites of a tobacco-specific lung carcinogen in children exposed to secondhand or thirdhand tobacco smoke in their homes
    Janet L Thomas
    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Cancer Epidemiol Biomarkers Prev 20:1213-21. 2011
    ..There is limited information in the literature on levels of total NNAL in children exposed to SHS...
  3. pmc The ratio of a urinary tobacco-specific lung carcinogen metabolite to cotinine is significantly higher in passive than in active smokers
    Rachel I Vogel
    Masonic Cancer Center, University of Minnesota, Minneapolis, USA
    Biomarkers 16:491-7. 2011
    ..The total NNAL:total cotinine (×10(3)) ratio may provide an improved biomarker for evaluating the health effects of passive smoking...
  4. pmc The sphingolipid degradation product trans-2-hexadecenal forms adducts with DNA
    Pramod Upadhyaya
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Biochem Biophys Res Commun 424:18-21. 2012
    ..Thus, our findings suggest that trans-2-hexadecenal produced endogenously by sphingosine 1-phosphate lyase can react directly with DNA forming aldehyde-derived DNA adducts with potentially mutagenic consequences...
  5. pmc Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosonornicotine in humans
    Aleksandar Knezevich
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Nicotine Tob Res 15:591-5. 2013
    ..Although the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction could also occur in the oral cavity in the presence of bacteria that catalyze nitrosation at neutral pH...
  6. pmc Lung carcinogenesis by tobacco smoke
    Stephen S Hecht
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Int J Cancer 131:2724-32. 2012
    ..37 million deaths per year...
  7. pmc Levels of (S)-N'-nitrosonornicotine in U.S. tobacco products
    Irina Stepanov
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Nicotine Tob Res 15:1305-10. 2013
    ..Of its two enantiomers, (S)-NNN exhibits higher tumorigenic potency than (R)-NNN. There is no information available on the levels of (S)-NNN in various tobacco products currently marketed in the United States...
  8. pmc Analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing DNA adducts in human exfoliated oral mucosa cells by liquid chromatography-electrospray ionization-tandem mass spectrometry
    Irina Stepanov
    Masonic Cancer Center and Division of Environmental Health Sciences, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, United States
    Chem Res Toxicol 26:37-45. 2013
    ..73, p < 0.0001). Potentially, the method can be applied in studies of individual susceptibility to tobacco-induced cancers in humans. ..
  9. pmc (S)-N'-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats
    Silvia Balbo
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Carcinogenesis 34:2178-83. 2013
    ....
  10. pmc Tobacco-specific N-nitrosamine exposures and cancer risk in the Shanghai Cohort Study: remarkable coherence with rat tumor sites
    Irina Stepanov
    Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN Masonic Cancer Center, University of Minnesota, Minneapolis, MN
    Int J Cancer 134:2278-83. 2014
    ....
  11. pmc High throughput liquid and gas chromatography-tandem mass spectrometry assays for tobacco-specific nitrosamine and polycyclic aromatic hydrocarbon metabolites associated with lung cancer in smokers
    Steven G Carmella
    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 26:1209-17. 2013
    ..The amount of PheT in smokers' urine was (mean ± SD) 1.43 ± 2.16 pmol/mL (N = 2613). The methodology described here should be widely applicable in future studies of tobacco use and cancer. ..
  12. pmc Thirdhand tobacco smoke: a tobacco-specific lung carcinogen on surfaces in smokers' homes
    Janet L Thomas
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN
    Nicotine Tob Res 16:26-32. 2014
    ..While previous studies have demonstrated the presence of nicotine and various other constituents of tobacco smoke on surfaces in smokers' homes, none has investigated the presence of tobacco-specific carcinogens...
  13. pmc Evidence for endogenous formation of the hepatocarcinogen N-nitrosodihydrouracil in rats treated with dihydrouracil and sodium nitrite: a potential source of human hepatic DNA carboxyethylation
    Mingyao Wang
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Chem Biol Interact 206:83-9. 2013
    ..Development of methodology for analysis of 7-CEGua in human leukocyte DNA is also reported, which will allow testing of this hypothesis in epidemiologic and clinical studies...
  14. pmc Quantitation of pyridyloxobutyl-DNA adducts in tissues of rats treated chronically with (R)- or (S)-N'-nitrosonornicotine (NNN) in a carcinogenicity study
    Lijiao Zhao
    College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
    Chem Res Toxicol 26:1526-35. 2013
    ....
  15. pmc Urinary tobacco smoke-constituent biomarkers for assessing risk of lung cancer
    Jian Min Yuan
    Authors Affiliations Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
    Cancer Res 74:401-11. 2014
    ....
  16. ncbi Fifty years of tobacco carcinogenesis research: from mechanisms to early detection and prevention of lung cancer
    Stephen S Hecht
    University of Minnesota, 2231 6th Street Southeast, Room 2 148 CCRB, Minneapolis, MN 55455 Phone 612 624 7604 Fax 612 624 3869 and Eva Szabo, Lung and Upper Aerodigestive Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, NIH, HHS, 9609 Medical Center Drive, Room 5E 102, Bethesda, MD 20892
    Cancer Prev Res (Phila) 7:1-8. 2014
    ..Collectively, research performed since the 1964 Report demonstrates unequivocally that the majority of deaths from lung cancer are preventable...
  17. pmc Formation and distribution of NNK metabolites in an isolated perfused rat lung
    Laura A Maertens
    College of Pharmacy, Department of Pharmaceutics, University of Minnesota, 308 Harvard Street SE, 9 149B Weaver Densford Hall, Minneapolis, MN 55455, USA
    Drug Metab Dispos 38:752-60. 2010
    ..Pyridylhydroxybutyl-DNA adducts were not detected in any of the treatment groups. Thus, the IPRL system is useful in determining pulmonary metabolism and DNA adduct formation separate from other metabolizing organs...
  18. pmc The influence of repair pathways on the cytotoxicity and mutagenicity induced by the pyridyloxobutylation pathway of tobacco-specific nitrosamines
    Li Li
    Division of Environmental Health Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 22:1464-72. 2009
    ..Together, these data support a hypothesis that the pyridyloxobutylation pathway generates multiple mutagenic and toxic adducts...
  19. pmc Analysis of 23 polycyclic aromatic hydrocarbons in smokeless tobacco by gas chromatography-mass spectrometry
    Irina Stepanov
    Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 23:66-73. 2010
    ..Urgent measures are required from the U.S. tobacco industry to modify manufacturing processes so that the levels of these toxicants and carcinogens in U.S. moist snuff are greatly reduced...
  20. pmc Applying tobacco carcinogen and toxicant biomarkers in product regulation and cancer prevention
    Stephen S Hecht
    Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 23:1001-8. 2010
    ....
  21. pmc Evolution of research on the DNA adduct chemistry of N-nitrosopyrrolidine and related aldehydes
    Stephen S Hecht
    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
    Chem Res Toxicol 24:781-90. 2011
    ....
  22. pmc Carcinogenic tobacco-specific N-nitrosamines in US cigarettes: three decades of remarkable neglect by the tobacco industry
    Irina Stepanov
    Masonic Cancer Center and Tobacco Use Research Programs, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Tob Control 21:44-8. 2012
    ..There is no information available on current TSNA levels in tobacco of various cigarettes available in the US, particularly in the newer varieties introduced over the past decade...
  23. pmc Chemoprevention of lung carcinogenesis in addicted smokers and ex-smokers
    Stephen S Hecht
    Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street South East, Minneapolis, Minnesota 55455, USA
    Nat Rev Cancer 9:476-88. 2009
    ..It seems likely that logically constructed mixtures of these agents, developed from the ground up, will be necessary for the prevention of lung carcinogenesis...
  24. pmc Clear differences in levels of a formaldehyde-DNA adduct in leukocytes of smokers and nonsmokers
    Mingyao Wang
    Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Cancer Res 69:7170-4. 2009
    ....
  25. pmc Presence of the carcinogen N'-nitrosonornicotine in the urine of some users of oral nicotine replacement therapy products
    Irina Stepanov
    Masonic Cancer Center and Transdisciplinary Tobacco Use Research Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Cancer Res 69:8236-40. 2009
    ..Given the carcinogenicity of NNN and the frequent use of nicotine gum as a smoking cessation aid, further studies are needed so that preventive measures can be developed...
  26. ncbi Metabolism of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone to its biomarker total NNAL in smokeless tobacco users
    Stephen S Hecht
    The Cancer Center and Transdisciplinary Tobacco Use Research Center, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA
    Cancer Epidemiol Biomarkers Prev 17:732-5. 2008
    ..The results of this study also indicate that metabolic activation of NNK to intermediates that can react with DNA is its major pathway of metabolism in smokeless tobacco users...
  27. ncbi Uptake of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by Moldovan children
    Irina Stepanov
    The Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA
    Cancer Epidemiol Biomarkers Prev 15:7-11. 2006
    ..These results should be useful in heightening the awareness of the dangers of smoking and ETS exposure in this eastern European country...
  28. pmc Quantitation of pyridyloxobutyl DNA adducts in nasal and oral mucosa of rats treated chronically with enantiomers of N'-nitrosonornicotine
    Siyi Zhang
    Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, MMC 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 22:949-56. 2009
    ..Our results also support the potential importance of NNN as an oral carcinogen in people who use smokeless tobacco products...
  29. pmc Analysis of pyridyloxobutyl and pyridylhydroxybutyl DNA adducts in extrahepatic tissues of F344 rats treated chronically with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    Siyi Zhang
    Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, MMC 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 22:926-36. 2009
    ....
  30. pmc Comparative levels of O6-methylguanine, pyridyloxobutyl-, and pyridylhydroxybutyl-DNA adducts in lung and liver of rats treated chronically with the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    Pramod Upadhyaya
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Drug Metab Dispos 37:1147-51. 2009
    ..The results of this study demonstrate that substantial amounts of O(6)-methyl-G are formed at various time points in lung and liver DNA of rats treated chronically with NNK, supporting its role in carcinogenesis...
  31. ncbi Cigarette smoking: cancer risks, carcinogens, and mechanisms
    Stephen S Hecht
    The Cancer Center, University of Minnesota, Box 806 Mayo, 420 Delaware Street SE, Minneapolis, MN, USA
    Langenbecks Arch Surg 391:603-13. 2006
    ..Cigarette smoking causes about 30% of all cancer mortality in developed countries. Although smoking is decreasing in developed countries, it is increasing in some developing countries...
  32. ncbi A biomarker of exposure to environmental tobacco smoke (ETS) and Ernst Wynder's opinion about ETS and lung cancer
    Stephen S Hecht
    The Cancer Center, University of Minnesota, Mayo Mail Code 806, Minneapolis, MN 55455, USA
    Prev Med 43:256-60. 2006
    ..These studies strongly support the epidemiologic data demonstrating that ETS exposure causes lung cancer in non-smokers and have likely had an impact on tobacco control...
  33. ncbi Tobacco-specific nitrosamines in new tobacco products
    Irina Stepanov
    The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Nicotine Tob Res 8:309-13. 2006
    ..These results demonstrate that TSNA levels in new tobacco products range from relatively low to comparable with those found in some conventional brands...
  34. pmc Quantitation of pyridyloxobutyl DNA adducts of tobacco-specific nitrosamines in rat tissue DNA by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry
    Yanbin Lao
    Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 19:674-82. 2006
    ....
  35. pmc Identification of adducts formed in the reaction of 5'-acetoxy-N'-nitrosonornicotine with deoxyguanosine and DNA
    Pramod Upadhyaya
    The Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 19:426-35. 2006
    ..These results provide the first structural characterization of DNA adducts that can be formed by 5'-hydroxylation of NNN...
  36. ncbi Comparative analysis of tobacco-specific nitrosamines and total N-nitroso compounds in moldovan cigarette tobacco
    Irina Stepanov
    The Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA
    J Agric Food Chem 53:8082-6. 2005
    ..66; P < 0.0001). These findings demonstrate that current technologies involved in the manufacture of some blended cigarettes create conditions that favor N-nitrosation of alkaloids and other tobacco constituents...
  37. ncbi Mass spectrometric analysis of relative levels of pyridyloxobutylation adducts formed in the reaction of DNA with a chemically activated form of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    Shana J Sturla
    The Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, MN 55455, USA
    Chem Res Toxicol 18:1048-55. 2005
    ....
  38. ncbi Metabolic activation of the tobacco carcinogen 4-(methylnitrosamino)-(3-pyridyl)-1-butanone by cytochrome P450 2A13 in human fetal nasal microsomes
    Hansen L Wong
    The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Chem Res Toxicol 18:913-8. 2005
    ..The results are also the first to demonstrate high efficiency NNK alpha-hydroxylation in a human tissue...
  39. ncbi Carcinogenicity studies of inhaled cigarette smoke in laboratory animals: old and new
    Stephen S Hecht
    The Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street, SE, Minneapolis, MN 55455, USA
    Carcinogenesis 26:1488-92. 2005
    ..This commentary attempts to put the new results in perspective with the existing literature on cigarette smoke inhalation studies in animals and discusses strengths, limitations and possible applications of available models...
  40. ncbi Tobacco-specific nitrosamines and their pyridine-N-glucuronides in the urine of smokers and smokeless tobacco users
    Irina Stepanov
    The Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA
    Cancer Epidemiol Biomarkers Prev 14:885-91. 2005
    ....
  41. ncbi Tobacco-specific nitrosamines in smokeless tobacco products marketed in India
    Irina Stepanov
    The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Int J Cancer 116:16-9. 2005
    ..The results of our study demonstrate that exposure to substantial amounts of carcinogenic tobacco-specific nitrosamines through use of smokeless tobacco products remains a major problem in India...
  42. pmc Investigation of the reaction of myosmine with sodium nitrite in vitro and in rats
    Stephen S Hecht
    The Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 20:543-9. 2007
    ..The results of this study do not support the hypothesis that exposure to dietary myosmine could lead to HPB-releasing DNA or Hb adducts in humans...
  43. pmc Formation and accumulation of pyridyloxobutyl DNA adducts in F344 rats chronically treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and enantiomers of its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    Yanbin Lao
    Department of Medicinal Chemistry, and the Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 20:235-45. 2007
    ....
  44. pmc Analysis of pyridyloxobutyl DNA adducts in F344 rats chronically treated with (R)- and (S)-N'-nitrosonornicotine
    Yanbin Lao
    Department of Medicinal Chemistry, and the Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 20:246-56. 2007
    ....
  45. pmc Evidence for endogenous formation of N'-nitrosonornicotine in some long-term nicotine patch users
    Irina Stepanov
    Masonic Cancer Center, University of Minnesota, 420 Delaware Street SE Mayo Mail Code 806, Minneapolis, MN 55455, USA
    Nicotine Tob Res 11:99-105. 2009
    ..Nitrosation of nicotine or its metabolites in the human body could lead to formation of the 2 carcinogenic tobacco-specific nitrosamines-N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)...
  46. pmc Mitochondrial DNA adducts in the lung and liver of F344 rats chronically treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and (S)-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    Irina Stepanov
    Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 22:406-14. 2009
    ..The results support the hypothesis that preferential binding of tobacco carcinogens to mtDNA of the lung might be functionally important in the development of smoking-induced lung cancer...
  47. pmc New and traditional smokeless tobacco: comparison of toxicant and carcinogen levels
    Irina Stepanov
    Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Nicotine Tob Res 10:1773-82. 2008
    ..The large variation in the levels of some toxicants and carcinogens analyzed here indicates that more effort is required from the U.S. tobacco industry to further reduce their amounts in new and traditional smokeless tobacco products...
  48. pmc Extensive metabolic activation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers
    Irina Stepanov
    The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Cancer Epidemiol Biomarkers Prev 17:1764-73. 2008
    ....
  49. pmc Quantitation of pyridylhydroxybutyl-DNA adducts in liver and lung of F-344 rats treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and enantiomers of its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    Pramod Upadhyaya
    Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 21:1468-76. 2008
    ....
  50. pmc Detection and quantitation of N'-nitrosonornicotine in human toenails by liquid chromatography-electrospray ionization-tandem mass spectrometry
    Irina Stepanov
    The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Cancer Epidemiol Biomarkers Prev 17:945-8. 2008
    ..58; P = 0.05). The results of this study show the feasibility of quantifying NNN in human toenails, providing a potentially useful new biomarker of tobacco carcinogen exposure...
  51. pmc Progress and challenges in selected areas of tobacco carcinogenesis
    Stephen S Hecht
    University of Minnesota Cancer Center, MMC 806, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 21:160-71. 2008
    ..It is hoped that a better understanding of mechanisms of tobacco-induced cancer will lead to new and useful approaches for the prevention of lung cancer and other cancers caused by tobacco use...
  52. ncbi Development of liquid chromatography electrospray ionization tandem mass spectrometry methods for analysis of DNA adducts of formaldehyde and their application to rats treated with N-nitrosodimethylamine or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    Mingyao Wang
    University of Minnesota Cancer Center, MMC 806, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA
    Chem Res Toxicol 20:1141-8. 2007
    ....
  53. ncbi Endogenous formation of N'-nitrosonornicotine in F344 rats in the presence of some antioxidants and grape seed extract
    Diana Porubin
    Department of Industrial and Ecological Chemistry, Moldova State University, 60 A Mateevici Street, Chisinau, Moldova
    J Agric Food Chem 55:7199-204. 2007
    ..This is the first study that demonstrates endogenous NNN formation in rats treated with nornicotine and sodium nitrite and effective inhibition of this process by ascorbic acid, dixydroxyfumaric acid, and catechin...
  54. ncbi Relationship of human toenail nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol to levels of these biomarkers in plasma and urine
    Irina Stepanov
    The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
    Cancer Epidemiol Biomarkers Prev 16:1382-6. 2007
    ..53; P = 0.005). The results of this study provide essential validation data for the use of toenail biomarkers in investigations of the role of chronic tobacco smoke exposure in human cancer...
  55. ncbi Urinary biomarkers to assess exposure of cats to environmental tobacco smoke
    Elizabeth A McNiel
    University of Minnesota Cancer Center, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA
    Am J Vet Res 68:349-53. 2007
    ..To evaluate the use of urinary biomarkers to assess exposure of cats to environmental tobacco smoke (ETS)...
  56. ncbi Cytochrome P450 enzymes as catalysts of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco specific carcinogen
    John R Jalas
    Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    Chem Res Toxicol 18:95-110. 2005