Abstract 3471: Reciprocal roles of cytochromes P4501A1 and 1A2 in polycyclic aromatic hydrocarbon (PAH)-mediated tumorigenesis in mice: Implications for lung cancer in humans

Abstract

Abstract Humans are constantly exposed to environmental carcinogenic polycyclic aromatic hydrocarbons (PAHs) through cigarette smoke, diesel exhausts, charcoal-broiled meats, etc. Cytochrome P4501A (CYP1A) enzymes play important roles in the activation of PAHs such as 3-methylcholanthrene (MC) to carcinogenic DNA-binding metabolites. The resulting DNA adducts may lead to mutations of tumor suppressor genes such as p53, thereby leading to tumorigenesis. In this study, we tested the hypothesis that CYP1A1 and 1A2 have reciprocal roles in PAH-mediated 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 in regard to lung tumor multiplicities and sizes of tumors. 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. Also, the tumor sizes were much larger in the Cyp1a2-null mice, compared to the much smaller sizes in the Cyp1a1-null mice. 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. 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 plays an important role in the protection 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. Thus, CYP1a1-null and Cyp1a2-null mice could be developed as novel animal models for future cancer prevention and/or therapeutic intervention in humans exposed to environmental PAHs. (Supported by NIH grant ES009132.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3471.