Abstract 3448: Synergistic effect of benzo(a)pyrene (BaP) and dietary fat on biotransformation enzymes, DNA adducts and colon tumors in ApcMin mice

Abstract

Abstract Studies in our laboratory thus far have shown formation of colon tumors in ApcMin mice subsequent to ingestion of fat containing BaP, an environmental carcinogen. These findings have human health relevance in that around 60,000 lives/year are lost to colon cancer in US alone. Diet and environment have been implicated in the development of sporadic colon tumors. Since biotransformation of toxicants is one of the factors that trigger carcinogenesis, the objective of this study was to determine how dietary fat potentiates the development of colon tumors through altered BaP biotransformation, using the ApcMin mouse model. Benzo(a)pyrene was administered to ApcMin mice in unsaturated- (peanut oil) and saturated- (coconut oil) fats at doses of 50 and 100 μg/kg via oral gavage over a 60-day period. Blood, colon and liver were collected at the end of exposure period. The expression of BaP biotransformation enzymes (CYP1A1, CYP1B1 and GST) in liver and colon were assayed at the level of mRNA and activities. Tissue samples were analyzed by reverse phase-HPLC for BaP metabolites, and 32P-postlabeling method for BaP- DNA adducts. BaP exposure through dietary fat altered its biotransformation in a dose-dependent manner, with 100 μg/kg dose group registering an elevated expression of BaP biotransformation enzymes, greater concentration of BaP metabolites, BaP-DNA adducts and more adenomas compared to the 50 μg/kg dose group (p < 0.05). This effect was more pronounced for saturated fat group compared to unsaturated fat group (p < 0.05). These findings establish that saturated fat contributes to sustained induction of BaP biotransformation enzymes and extensive metabolism of this carcinogen. As a consequence, the reactive metabolites such as epoxides and quinones generated in colon bind with DNA, and form adducts resulting in colon tumors in a long term exposure situation (funded by NIH grants S11ES014156, 1F31ES017391-01, 5T32 HL007735-14 and RO3CA130112-01). 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 3448.