Abstract 4816: Tobacco smoke modulates estrogen metabolism in the mouse lung

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Tobacco smoke is the major risk factor for lung cancer; the leading cause of cancer death in both men and women in the US and worldwide. Recent studies suggest that the female hormone estrogen promotes lung cancer development. However, the relationship between tobacco smoke exposure and estrogen is not well studied. Previous data from our lab showed that whole-body exposure to tobacco smoke induced the expression of the phase I detoxification enzyme cytochrome P450 1B1 (CYP1B1) within the lungs of female A/J mice. CYP1B1 activates polyaromatic hydrocarbons in tobacco smoke and also converts estrogen to catechol metabolites, in particular 4-hydroxy estrogens (4-OHEs), which are known to be carcinogenic. The goal of this study was to characterize the profile of estrogen metabolites within the lung using a novel high-performance liquid chromatography/electrospray ionization/tandem mass spectrometry (HPLC/ESI/MS/MS) protocol. Three estrogens (E1, E2 and E3) and five estrogen metabolites (2-OHE1, 4-OHE1, 4-OHE2, 2-OMeE1 and 2-OMeE2) were detected in perfused murine lungs, with 4-OHE1 identified as the most abundant estrogen metabolite. The levels of both 4-OHE1 and 4-OHE2 were 2-fold higher within the lungs of female mice as compared to those of males. This elevation was maintained when total 4-OHE levels were normalized to total estrogen (sum of estrogen and its metabolites, p=0.009). In contrast, no gender difference was observed in 2-OHE1 levels. This estrogen metabolite profile is consistent with the results from gene expression analyses, which revealed that the ratio of CYP1B1 to CYP1A1 transcripts (CYP1A1 produces 2-OHE) was elevated (2-fold) in females as compared to males (p=0.05). To assess the impact of tobacco smoke on the profile of estrogen metabolites within the lung, female mice were exposed to tobacco smoke for 8 weeks and estrogen metabolite levels were measured by HPLC/ESI/MS/MS. As expected, the levels of 4-OHEs were significantly higher within the lungs of mice exposed to tobacco smoke (4-fold for 4-OHE1 and 2-fold for 2-OHE2) as compared to controls exposed to filtered air (p=0.00003 and 0.0007, respectively). Interestingly, the level of total 2-OMeE, a putative protective estrogen metabolite, was decreased to 70% of controls in mice exposed to tobacco smoke (p=0.005) while 2-OHE levels were comparable in control and smoke-exposed animals. These results suggest that tobacco smoke accelerates the production of carcinogenic 4-OHEs within the lung; metabolites that could potentially contribute to lung tumor development. Furthermore, CYP1B1 may represent a molecular target for therapeutic intervention in lung tumor formation. Future studies will focus on comparing the profile of estrogen metabolites in human lung tissue from never smokers and current smokers. This work was supported by funds from the Estate of Jane Villon and the Kitty Jackson Fund. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4816. doi:1538-7445.AM2012-4816