Abstract 4572: Western diet enhances benzo(a)pyrene [B(a)P]-induced colon tumorigenesis in the PIRC rat model via cytochrome P450 drug metabolizing enzymes

Abstract

Abstract Colorectal cancer ranks third in terms of mortalities in the United States, with 50,000 deaths per year and around 140,000 new cases expected to be diagnosed in this year. Epidemiological studies have pointed out that obese people have a higher risk for colon cancer. It is well known that overweight or obesity is induced by excess energy intake from dietary fat. Additionally, consumption of well-done red meat and saturated fats, rich in food-borne environmental toxicants such as polycyclic aromatic hydrocarbons (PAHs) has also been implicated as one of the causative factors for sporadic colon cancer. Therefore, the objective of this study was to investigate the effect of dietary fat type on B(a)P-induced colon cancer in an adult male rat model, the Polyposis In the Rat Colon (PIRC) kindred type. Specifically, this research sets out to determine whether the colon polyp burden potentiated by WD when exposed to B(a)P employed drug metabolizing enymes (cytochrome P450 family) to enhance the effect of the WD. Groups of PIRC rats (n = 5) were fed with AIN-76A regular diet (RD) or Western diet (WD) and received 25, 50 and 100 μg B(a)P/kg body wt. via oral gavage for 60 days. Rats fed the diets alone, but no B(a)P, served as controls. Subsequent to exposure, rats were sacrificed; colons, liver and other tissues were retrieved and preserved in 10% formalin for observation of gross pathological changes. Colon and liver samples were analyzed for activation of drug metabolizing enzymes (DMEs) CYP1A1, CYP1B1 and GST. Benzo(a)pyrene metabolite concentrations were measured using a HPLC equipped with UV and fluorescence detectors. An increased incidence of adenomas and high grade dysplasia were encountered in rats that were fed with WD compared to RD and controls (p < 0.05). The colon tumor counts were more in B(a)P + WD rats compared to their B(a)P + RD counterparts, and also exhibited a B(a)P dose-response relationship, with 100 μg B(a)P/kg registering greater counts. Adenomas with high grade dysplasia were prominent in B(a)P + WD rats compared to B(a)P + RD rats. Western diet consumption increased DME activation among rats that were given B(a)P + WD with marked increase in enzyme expression and B(a)P metabolite concentrations in rats that were administered 100 μg/kg B(a)P + WD (p < 0.05) compared to other treatment groups. Our results demonstrate that WD accelerates the development of colon tumors induced by B(a)P, utilizing cytochrome P450 metabolic pathways. This research was supported from NIH grants 1F31ESO2407901, 5RO1CA142845-04, 5R25GM059994-11, and Southern Regional Education Board. Note: This abstract was not presented at the meeting. Citation Format: Kelly Harris, Mohammad Niaz, Mary Washington, Aramandla Ramesh. Western diet enhances benzo(a)pyrene [B(a)P]-induced colon tumorigenesis in the PIRC rat model via cytochrome P450 drug metabolizing enzymes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4572. doi:10.1158/1538-7445.AM2015-4572