Abstract A69: Pilot study of the effects of indole-3-carbinol on deuterated phenanthrene metabolism in smokers

Abstract

Abstract Background/Purpose: Polycyclic aromatic hydrocarbons (PAH), widely considered as critical causative agents of tobacco-related lung cancer, are found in high levels in tobacco smoke and require metabolic activation to exert their carcinogenic effects. The development of urinary biomarkers of PAH metabolism using the more abundant and generally non-carcinogenic phenanthrene (Phe) as a surrogate of the prototypic carcinogenic PAH benzo[a]pyrene (BaP) has provided a reliable tool to characterize the uptake and metabolism of BaP in smokers. There is wide inter-individual variation in PheT metabolism. Furthermore, smokers who are more efficient metabolic activators of Phe appear to have a higher risk of developing lung cancer in prospective case-control studies. We examined the effects of indole-3-carbinol (I3C), a compound arising from cruciferous vegetables shown to possess anti-cancer activity, in modifying Phe metabolism. We hypothesized that I3C might have a chemopreventive effect in cigarette smokers by abrogating the metabolic activation and/or detoxification of [D10]Phe. Procedures: Ten micrograms of [D10]Phe was administered via inhalation of a smoked cigarette prior to and after 7 days if I3C 400 mg po BID. Plasma and urine samples were collected at baseline and for 48 hours following [D10]Phe administration. Deuterated phenanthrene tetraol ([D10]PheT, a reflection of uptake and metabolic activation via the diol epoxide pathway), and deuterated phenanthrol ([D10]HOPhe, a reflection of detoxification and elimination) were quantified in urine and plasma before and after I3C and compared. Results: A total of 8 subjects completed the study procedures, 6 females and 2 males. Subject 8 was clearly an outlier and was excluded from analysis. One-sample t-test was used to compare the mean difference in [D10]PheT and the mean difference in [D10]HOPhe among the group before and after I3C. The reduction in [D10]PheT in urine was significant (one-sample t-test, p=.023), although only marginally so in plasma (=.083). [D10]PheT AUC was not reduced (p=.23). [D10]HOPhe was generally reduced but not significantly (p=.15). Correlation between 6-hour and 48-hour [D10]PheT and [D10]HOPhe was very strong (r=.873; p=.010 and r=.968;p<.001, respectively). Conclusion: I3C may be an effective chemopreventive agent in tobacco-related lung cancer by reducing the metabolic activation of carcinogenic PAH. A larger, definitive study is needed to confirm these results. Citation Format: Naomi Fujioka, Yan Zhong, J. Bradley Holchalter, Diane Rauch, Joni J. Jensen, Chap T. Le, Dorothy K. Hatsukami, Stephen S. Hecht. Pilot study of the effects of indole-3-carbinol on deuterated phenanthrene metabolism in smokers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A69.