Pilot Project: 3 "Dietary Fat Potentiation of B(a)P Induced Colon Cancer"

Meharry Medical College, Nashville TN

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Abstract

Benzo(a)pyrene (BaP) is a lipophilic, widely distributed environmental toxicant that belongs to the polycyclic[unreadable] aromatic hydrocarbon (PAH) family of compounds. This chemical is known to cause toxicity and cancer in[unreadable] various organ systems. Our preliminary studies have shown that exposure of rats to BaP and other PAHs[unreadable] cause induction of cytochrome P450 (CYP) family of enzymes resulting in the formation and distribution of[unreadable] reactive metabolites in plasma and target tissues. Our studies have also shown that dietary exposure of rats[unreadable] to PAHs via saturated fat results in increased concentration of reactive metabolites, which stayed in target[unreadable] tissues for a longer time causing DNA damage compared to those that received these chemicals through[unreadable] unsaturated fat. Our hypothesis is that dietary fat contributes to BaP-induced colon carcinogenesis through[unreadable] CYP mediated epoxide and quinone pathways. The rationale behind this study is that every year 56,000[unreadable] deaths are attributed to colorectal cancer in United States of America and in a great majority of the cases[unreadable] surveyed, consumption of well-done red meat and other saturated fats, rich in PAHs were implicated as a[unreadable] possible causative factor. This implies that formation and progression of colon tumors depends on altered[unreadable] BaP biotransformation by the type of dietary lipids ingested. We intend to test our hypothesis by studying the[unreadable] effects of oral exposure of adult Apc Min mice to BaP in saturated fat, using the following specific aims: 1.[unreadable] Investigate the potentiating effect of dietary fat on BaP-induced adenomas in small intestine and colon of[unreadable] adult Apc Min mice; 2. Determine the dietary fat induced alteration of BaP biotransformation enzyme[unreadable] activities and pharmacokinetics in Ape Min mice; 3. Assess the contribution of dietary fat to BaP-DNA adduct[unreadable] formation and persistence in Ape Min mice; 4. Evaluate the role of dietary fat in BaP-induced oxidative[unreadable] damage and isoprostane production in Apc Min mice. This pilot project is expected to provide new .[unreadable] information to conduct mechanism-based chemoprevention studies for colorectal carcinogenesis. In other[unreadable] words, information gained from these studies will help to understand the contribution of consumption of fatty[unreadable] foods contaminated with toxic chemicals towards the development of colorectal cancers in humans.[unreadable] Furthermore, the knowledge gained from these studies will help to synthesize drugs that could be used to[unreadable] prevent the development of tumors in colon.