Individual susceptibility plays an important role in cancer development in humans exposed to chemical carcinogens, thus identification of high-risk individuals is critical in cancer prevention and therapy. Benzo[a]pyrene (BaP), an important polycyclic aromatic hydrocarbon (PAH) in tobacco smoke and the environment, is considered carcinogenic to humans by the International Agency for Research on Cancer. BaP requires metabolic activation by the diol epoxide pathway to exert its carcinogenic effect, and this process differs greatly among individuals, who can’t be identified based on exposure measurements only. In this study, we used deuterated phenanthrene ([D10]Phe), a non-carcinogenic PAH with structural features and enzymology profile similar to that of BaP, as a probe substrate. The bioactivation of Phe bythe diol epoxide pathway yields the urinary metabolites phenanthrene dihydrodiol(Phe-Diol), phenanthrene tetraol(PheT) and phenanthrene quinone (PheQ), whereas phenanthrols (HOPhe) signify detoxification. A previous prospective epidemiological study has confirmed the statistically significant relationship between urinary levels of PheT and lung cancer risk. PheQ has been associated with the generation of reactive oxygen species (ROS) and oxidative damage, while Phe-Diol is the precursor of PheT and PheQ. We administered [D10]Phe, with FDA approval, to smokers (N=137, 10 µg oral dose) and nonsmokers (N=89, 1 µg oral dose) and quantified the excretion of its urinary metabolites noted above. The smoking status of all subjects was determined by urinary cotinine. We have already shown that this metabolism phenotyping approach is practical, accurate and precise. There were great variations among subjects in conversion of [D10]Phe to [D10]Phe-1,2-diol (31-fold/497-fold in 10 µg/1 µg dose group), [D10]PheT (51-fold/84-fold) and [D9]HOPhe (33-fold/84-fold), [D8]PheQ (18-fold/47-fold). We hypothesize that individuals who have a higher ratio of bioactivation metabolites ([D10]Phe-Diol+[D10]PheT+[D8]PheQ) to detoxification metabolites ([D9]HOPhe) are at higher risk for lung cancer. Oral cell genotyping of GSTs were also determined to explore genetic causes of individual differences. The results of this study promises to expand our understanding of metabolism of carcinogenic PAH in humans, thus providing new insights for human health risk assessment and lung cancer prevention.

Multiple deuterated phenanthrene metabolites as probes for the metabolism of carcinogenic PAHs in humans: Phenotyping, genotyping and potential application in human health risk assessment

2019 Fall National Meeting

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