Grant Number:	2R01CA092025-11 Interpret this number
Primary Investigator:	Hecht, Stephen
Organization:	University Of Minnesota
Project Title:	BENZO[A]PYRENE Metabolism: Phenotyping and Genotyping
Fiscal Year:	2012

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the U.S., resulting in more than 157,000 deaths in 2010. Ninety percent of this horrific toll is caused by cigarette smoking, yet only 11-24% of smokers will die from lung cancer. It is imperative that we find ways to identify, at a relatively young age, those smokers who are susceptible to lung cancer, so they can be targeted for intensive preventive interventions. We hypothesize that smokers who extensively metabolically activate lung carcinogens in cigarette smoke will be at highest risk for lung cancer. We have developed a unique and innovative phenotyping method to potentially identify these smokers. This method focuses on two types of carcinogens believed to play a significant role in lung cancer development in smokers: polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines, typified by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We use deuterated phenanthrene [D10]Phe, a non- carcinogenic PAH with structural features and enzymology profile similar to that of carcinogenic PAH, as a probe substrate. We administer this compound, with FDA approval, to smokers and quantify the excretion of its product of metabolic activation [D10]phenanthrene tetraol [D10]PheT, in urine. We have shown that this phenotyping approach is practical, accurate and precise. There is a 20-fold variation among smokers in conversion of [D10]Phe to [D10]PheT and we hypothesize that the smokers who carry out this conversion most extensively are at highest risk for lung cancer. In this proposal, we will extend our ongoing studies with the following specific aims: 1. Carry out a study in smokers to determine whether there is overlap between those who extensively metabolize [D10]Phe to [D10]PheT, activate NNK by ¿-hydroxylation, and inhale the greatest amount of tobacco smoke carcinogens as determined by nicotine metabolites. We hypothesize that there will be overlap among these extensive metabolism and exposure groups and that we can therefore identify these "triple risk" individuals. 2. Determine the pharmacokinetics of [D10]Phe in adolescents who have just started smoking and compare to our existing data on [D10]Phe metabolism in habitual smokers. 3. Determine the relationship between benzo[a]pyrene metabolism by the carcinogenic diol epoxide pathway and Phe metabolism in smokers. We hypothesize that the carcinogenic metabolism pathway of benzo[a]pyrene will correlate strongly with tetraol formation from Phe. 4. Further characterize the glutathione detoxification pathway of Phe by analysis of smokers' urine. The results of this proposal will vastly expand our understanding of lung carcinogen metabolism in smokers, thus providing new insights for tobacco control and lung cancer prevention. PUBLIC HEALTH RELEVANCE: Ninety percent of lung cancer, the leading cause of cancer death in the United States, is caused by cigarette smoking but only 11-24% of smokers get lung cancer. In this project, new methods are being developed which can potentially identify susceptible smokers at a young age. These smokers could be targeted for intensive smoking cessation measures to prevent lung cancer.




Ultrasensitive High-Resolution Mass Spectrometric Analysis of a DNA Adduct of the Carcinogen Benzo[a]pyrene in Human Lung.
Authors: Villalta P.W. , Hochalter J.B. , Hecht S.S. .
Source: Analytical Chemistry, 2017-12-05 00:00:00.0; 89(23), p. 12735-12742.
EPub date: 2017-11-17 00:00:00.0.
PMID: 29111668
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Investigation of the presence in human urine of mercapturic acids derived from phenanthrene, a representative polycyclic aromatic hydrocarbon.
Authors: Cheng G. , Zarth A.T. , Upadhyaya P. , Villalta P.W. , Balbo S. , Hecht S.S. .
Source: Chemico-biological Interactions, 2017-08-25 00:00:00.0; 274, p. 80-88.
EPub date: 2017-07-08 00:00:00.0.
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Quantitation of enantiomers of r-7,t-8,9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]-pyrene in human urine: evidence supporting metabolic activation of benzo[a]pyrene via the bay region diol epoxide.
Authors: Hecht S.S. , Hochalter J.B. .
Source: Mutagenesis, 2014 Sep; 29(5), p. 351-6.
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It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco.
Authors: Hecht S.S. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2014 Jul; 7(7), p. 639-47.
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Analysis of the benzene oxide-DNA adduct 7-phenylguanine by liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry-parallel reaction monitoring: application to DNA from exposed mice and humans.
Authors: Zarth A.T. , Cheng G. , Zhang Z. , Wang M. , Villalta P.W. , Balbo S. , Hecht S.S. .
Source: Chemico-biological Interactions, 2014-05-25 00:00:00.0; 215, p. 40-5.
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Authors: Yuan J.M. , Butler L.M. , Gao Y.T. , Murphy S.E. , Carmella S.G. , Wang R. , Nelson H.H. , Hecht S.S. .
Source: Carcinogenesis, 2014 Feb; 35(2), p. 339-45.
PMID: 24148823
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Urinary tobacco smoke-constituent biomarkers for assessing risk of lung cancer.
Authors: Yuan J.M. , Butler L.M. , Stepanov I. , Hecht S.S. .
Source: Cancer Research, 2014-01-15 00:00:00.0; 74(2), p. 401-11.
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Fifty years of tobacco carcinogenesis research: from mechanisms to early detection and prevention of lung cancer.
Authors: Hecht S.S. , Szabo E. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2014 Jan; 7(1), p. 1-8.
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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.
Authors: Carmella S.G. , Ming X. , Olvera N. , Brookmeyer C. , Yoder A. , Hecht S.S. .
Source: Chemical Research In Toxicology, 2013-08-19 00:00:00.0; 26(8), p. 1209-17.
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Tobacco smoke biomarkers and cancer risk among male smokers in the Shanghai cohort study.
Authors: Hecht S.S. , Murphy S.E. , Stepanov I. , Nelson H.H. , Yuan J.M. .
Source: Cancer Letters, 2013-06-28 00:00:00.0; 334(1), p. 34-8.
EPub date: 2013-06-28 00:00:00.0.
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Longitudinal study of [D10]phenanthrene metabolism by the diol epoxide pathway in smokers.
Authors: Hecht S.S. , Hochalter J.B. , Carmella S.G. , Zhang Y. , Rauch D.M. , Fujioka N. , Jensen J. , Hatsukami D.K. .
Source: Biomarkers : Biochemical Indicators Of Exposure, Response, And Susceptibility To Chemicals, 2013 Mar; 18(2), p. 144-50.
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Lung carcinogenesis by tobacco smoke.
Authors: Hecht S.S. .
Source: International Journal Of Cancer, 2012-12-15 00:00:00.0; 131(12), p. 2724-32.
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Phenanthrene metabolism in smokers: use of a two-step diagnostic plot approach to identify subjects with extensive metabolic activation.
Authors: Wang J. , Zhong Y. , Carmella S.G. , Hochalter J.B. , Rauch D. , Oliver A. , Jensen J. , Hatsukami D.K. , Upadhyaya P. , Hecht S.S. , et al. .
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Urinary levels of volatile organic carcinogen and toxicant biomarkers in relation to lung cancer development in smokers.
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Research opportunities related to establishing standards for tobacco products under the Family Smoking Prevention and Tobacco Control Act.
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Urinary levels of cigarette smoke constituent metabolites are prospectively associated with lung cancer development in smokers.
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Metabolism of [D10]phenanthrene to tetraols in smokers for potential lung cancer susceptibility assessment: comparison of oral and inhalation routes of administration.
Authors: Zhong Y. , Wang J. , Carmella S.G. , Hochalter J.B. , Rauch D. , Oliver A. , Jensen J. , Hatsukami D.K. , Upadhyaya P. , Zimmerman C. , et al. .
Source: The Journal Of Pharmacology And Experimental Therapeutics, 2011 Jul; 338(1), p. 353-61.
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Immediate consequences of cigarette smoking: rapid formation of polycyclic aromatic hydrocarbon diol epoxides.
Authors: Zhong Y. , Carmella S.G. , Upadhyaya P. , Hochalter J.B. , Rauch D. , Oliver A. , Jensen J. , Hatsukami D. , Wang J. , Zimmerman C. , et al. .
Source: Chemical Research In Toxicology, 2011-02-18 00:00:00.0; 24(2), p. 246-52.
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Quantitation of a minor enantiomer of phenanthrene tetraol in human urine: correlations with levels of overall phenanthrene tetraol, benzo[a]pyrene tetraol, and 1-hydroxypyrene.
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Source: Chemical Research In Toxicology, 2011-02-18 00:00:00.0; 24(2), p. 262-8.
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Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2006 Aug; 15(8), p. 1490-4.
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