Abstract 3579: Mechanistic roles of cytochrome P4501A1 and 1A2 in lung carcinogenesis mediated by polycyclyc aromatic hydrocarbons: Implications for lung cancer in humans .

Abstract

Abstract Humans are frequently exposed to polycyclic aromatic hydrocarbons (PAHs). Cytochrome P4501A (CYP1A) enzymes play important roles in the activation of PAHs such as 3-methylcholanthrene (MC) to DNA-binding metabolites, which in turn mediate carcinogenesis in target organs such as lung, breast, and skin. In this study, we tested the hypothesis that CYP1A1 and 1A2 play mechanistic roles in PAH-mediated carcinogenesis and tumorigenesis. Eight week-old female wild type (WT) (A/J) mice or mice lacking the gene for CYP1A1 or CYP1A2 on the A/J background were treated with a single dose of MC (40 μmol/kg), benzo[a]pyrene (BP), or vehicle (corn oil), and liver and lung tumors were studied after 28 weeks. While 100% of WT or Cyp1a2-null mice exposed to MC showed lung tumors after 28 weeks, about 80% of the Cyp1a1-null mice showed lung tumors. However, there were striking differences in the Cyp1a1-null and Cyp1a2-null mice in regard to lung tumor multiplicities. The WT mice treated with MC had about 15 lung tumors/animal. On the other hand, the Cyp1a2-null mice displayed about 40 lung tumors/animal, while the Cyp1a1-null mice showed about 2-3 tumors/mouse. Although BP was less potent in inducing lung tumors in the WT mice compared to MC, it was similar to MC In that tumors were suppressed in the Cyp1a1-null mice and augmented in the Cyp1a2-null mice. DNA adduct studies at early time points showed increased MC or BP adducts in lungs of Cyp1a2-null mice compared to WT mice, and decreased adduct formation in the Cyp1a1-null mice, supporting the hypothesis that DNA adducts are early biomarkers of PAH-mediated carcinogenesis. Immunohistochemical studies showed that CYP1A1 was overexpressed in the tumorous portions of the lung in the Cyp1a2-null or WT mice, compared to non-tumorous regions. These results suggest that CYP1A1 contributes to the formation of tumorigenesis by PAHs, while CYP1A2 protects against carcinogenesis mediated by PAHs, presumably through it role in PAH detoxification. In conclusion, our results strongly suggest that CYP1A1 and 1A2 could be novel candidates for cancer prevention and therapy though either inhibition of CYP1A1 or induction of CYP1A2. (Supported by NIH grant ES009132.) Citation Format: Bhagavatula Moorthy, Guodong Zhou, Lihua Wang, Weiwu Jiang. Mechanistic roles of cytochrome P4501A1 and 1A2 in lung carcinogenesis mediated by polycyclyc aromatic hydrocarbons: Implications for lung cancer in humans . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3579. doi:10.1158/1538-7445.AM2013-3579