Abstract 1587: Mechanistic role of cytochrome P4501B1 in DNA adduct formation by 3-methylcholanthrene in mice: Implications for lung cancer in humans

Abstract

Abstract Humans are frequently exposed to polycyclic aromatic hydrocarbons (PAHs). Cytochrome P450 (CYP)1A and 1B1 enzymes are known to 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 investigation, we tested the hypothesis that mice lacking the gene for Cyp1b1 will show attenuation of MC-DNA adduct formation, compared to WT mice. Eight week-old female wild type (WT) (C57BL/6J) mice or mice lacking the gene for Cyp1b1 were treated with MC (100 µmol/kg), once daily for 2 days, and animals sacrificed 1 day after the last treatment. DNA adducts from liver and lung genomic DNA were analyzed by the 32P-postabeling assay. Control animals received only the vehicle corn oil (CO). In WT mice, CO-treated group did not show any adducts, whereas MC-treated animals showed 11 adduct spots in the lung. In Cyp1b1-null mice, although there were no qualitative differences in the pulmonary adduct pattern, the levels of each adduct was markedly suppressed (25-90%), with total levels of adducts being about 15% of those formed in WT mice. In liver of WT as well as Cyp1b1-null mice, MC induced formation of 11 adducts, and the adduct pattern was similar to that of lung, but the total levels of adducts in WT mice were about a third of those seen in the lungs of the corresponding animals. In Cyp1b1-null mice, MC adducts were significantly decreased compared to WT mice, but the extent of attenuation in liver was lesser than that in lung. These results suggest that CYP1B1 plays a major role in formation of DNA adducts from MC. Because DNA adducts are pre-mutagenic lesions, our results are highly relevant to PAH-mediated pulmonary carcinogenesis. Our data suggest that CYP1B1 could be a molecular target for developing preventive and therapeutic strategies against lung cancer in humans. Citation Format: Bhagavatula Moorthy, Guodong Zhou, Lihua Wang, Sudha R. Kondraganti, Weiwu Jiang. Mechanistic role of cytochrome P4501B1 in DNA adduct formation by 3-methylcholanthrene in mice: Implications for lung cancer in humans. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1587. doi:10.1158/1538-7445.AM2014-1587