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. ? ? ?
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