Lung cancer is the leading cause of cancer death in the world. Cigarette smoking causes about 90% of lung cancer. Polycyclic aromatic hydrocarbons (PAH) are major causative agents for lung cancer in smokers. PAH require metabolic activation to exert their carcinogenic effects, and this differs greatly among individuals. It is hypothesized that smokers who metabolically activate PAH more effectively are at higher risk for lung cancer. This hypothesis has been widely tested in the literature by examining polymorphisms in genes involved in the metabolic activation and detoxification of PAH. The results of these studies have been mixed but do provide some evidence in support of the hypothesis. We believe that carcinogen metabolite phenotyping, the actual measurement of PAH metabolites in urine, would be a better method of identifying high risk smokers. Therefore, we have developed methods for the quantitation of phenanthrene (Phe) metabolites in urine. Phe is the simplest PAH with a bay region, a feature closely associated with carcinogenicity, and its metabolism is very similar to that of benzo[a]pyrene. Measurement of Phe metabolites in urine is practical for large studies. The major end-product of the metabolic activation pathway of Phe is r-1,t2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) while detoxification produces phenanthrols (HOPhe). We have developed the PheT:HOPhe ratio as a measure of individual metabolism of Phe. However, this ratio is quite variable in some individuals. We now propose to use deuterated Phe ([D10]Phe) as an improved way to assess individual metabolic activation of PAH. The use of [D10]Phe to monitor PAH metabolism in smokers is an innovative concept that has been approved by FDA.
Our specific aims are: 1. Determine and compare the pharmacokinetics of [D10]Phe in smokers after oral dosing and incorporation into cigarettes. 2. Determine the longitudinal stability of [D10]PheT levels in smokers to whom [D10]Phe has been administered. Determine levels of [D10]PheT and PheT:HOPhe ratios after cessation of smoking. Compare levels of [D10]PheT to PheT:HOPhe ratios in smokers. 3. Establish the quantitative pattern of [D10]Phe metabolism in smokers. 4. Determine the relationship between levels of [D10]PheT or PheT:HOPhe ratios and detection of bronchoepithelial metaplasia and dysplasia in smokers on whom screening bronchoscopies have been performed. The results of this study will greatly improve our understanding of PAH metabolism in humans and could ultimately lead to a predictive algorithm for lung cancer risk in smokers. Such information is vital for lung cancer prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092025-09
Application #
7857955
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Ellison, Gary L
Project Start
2001-07-24
Project End
2012-05-31
Budget Start
2010-07-07
Budget End
2011-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$338,679
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Cheng, Guang; Zarth, Adam T; Upadhyaya, Pramod et al. (2017) Investigation of the presence in human urine of mercapturic acids derived from phenanthrene, a representative polycyclic aromatic hydrocarbon. Chem Biol Interact 274:80-88
Hecht, Stephen S; Szabo, Eva (2014) Fifty years of tobacco carcinogenesis research: from mechanisms to early detection and prevention of lung cancer. Cancer Prev Res (Phila) 7:1-8
Zarth, Adam T; Cheng, Guang; Zhang, Zhaobin et al. (2014) 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. Chem Biol Interact 215:40-5
Hecht, Stephen S; Hochalter, Jon Bradley (2014) 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. Mutagenesis 29:351-6
Yuan, Jian-Min; Butler, Lesley M; Stepanov, Irina et al. (2014) Urinary tobacco smoke-constituent biomarkers for assessing risk of lung cancer. Cancer Res 74:401-11
Yuan, Jian-Min; Butler, Lesley M; Gao, Yu-Tang et al. (2014) Urinary metabolites of a polycyclic aromatic hydrocarbon and volatile organic compounds in relation to lung cancer development in lifelong never smokers in the Shanghai Cohort Study. Carcinogenesis 35:339-45
Hecht, Stephen S (2014) It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco. Cancer Prev Res (Phila) 7:639-47
Carmella, Steven G; Ming, Xun; Olvera, Natalie et al. (2013) 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. Chem Res Toxicol 26:1209-17
Hecht, Stephen S; Hochalter, J Bradley; Carmella, Steven G et al. (2013) Longitudinal study of [D10]phenanthrene metabolism by the diol epoxide pathway in smokers. Biomarkers 18:144-50
Hecht, Stephen S; Murphy, Sharon E; Stepanov, Irina et al. (2013) Tobacco smoke biomarkers and cancer risk among male smokers in the Shanghai cohort study. Cancer Lett 334:34-8

Showing the most recent 10 out of 40 publications