Abstract CN07-02: Polycyclic aromatic hydrocarbon tetraols: Potential phenotypic indicators of lung cancer susceptibility in smokers

Abstract

Abstract Polycyclic aromatic hydrocarbons (PAH) are believed to be among the major causative agents for lung cancer in smokers. PAH require metabolic activation to exert their carcinogenic effects, and one important pathway proceeds through a three-step metabolic sequence resulting in the formation of diol epoxides which react with DNA producing adducts that can cause mutations and initiate the carcinogenic process. Many studies demonstrate wide interindividual differences in PAH metabolism. Our working hypothesis is that individuals who metabolically activate PAH by the diol epoxide pathway more extensively will be at higher risk for lung cancer than those who are less proficient. We have used a phenotyping approach to investigate this hypothesis. In this approach, we use gas chromatographytandem mass spectrometry to quantify PAH tetraols, the major end products of the diol epoxide metabolic activation pathway, in plasma or urine. In one recent nested case-control study of 475 lung cancer cases and 475 controls, all smokers, in the Shanghai Cohort Study of over 18,000 men, we demonstrated a significant relationship to lung cancer of urinary levels of r,1-t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), the major end product of the diol epoxide pathway of phenanthrene, the simplest PAH with a bay region, a feature closely associated with carcinogenicity. With advances in mass spectrometry, we are now able to directly assess levels of tetraols resulting from diol epoxide formation from the prototypic carcinogenic PAH, benzo[a]pyrene. These studies demonstrated higher levels of this tetraol in the urine of smokers than non-smokers. Our approach to individual phenotyping of smokers uses a stable isotope labeled PAH, [D10]phenanthrene. Smokers either use cigarettes to which [D10]phenanthrene has been added, or take the substance orally. Plasma and urine are analyzed for the tetraol, [D10]PheT, the major end product of the diol epoxide metabolism pathway of phenanthrene. The results of these ongoing studies show a large interindividual variation in [D10]PheT production and demonstrate that this approach is feasible for identifying those individuals who extensively metabolize phenanthrene. These studies also showed for the first time that the three-step pathway resulting in formation of diol epoxides, as monitored by [D10]PheT, occurred with remarkable rapidity in all subjects. Levels of [D10]PheT in plasma of all subjects were maximal 15-30 min after smoking a cigarette containing [D10]phenanthrene, and decreased thereafter. These results demonstrate that the formation of a PAH diol epoxide occurs rapidly in smokers. Since PAH diol epoxides are mutagenic and carcinogenic, the results clearly demonstrate immediate negative health consequences of smoking which should serve as a major warning to anyone contemplating initiating tobacco use. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN07-02.