Intestinal Disposition of Chemoprevention Agents

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DESCRIPTION (provided by applicant): Dietary factors, particularly increased consumption of fruits and vegetables, can decrease the risk of developing cancer including gastrointestinal cancers among others. The presence of chemopreventive compounds in fruits and vegetables is believed to contribute to the role of diet in mitigating cancer risk. Many compounds with chemopreventive activity have been isolated from a host of edible plants (e.g., sulforaphane from broccoli and Brussels sprouts; resveratrol from grapes and peanuts; geraniol from lemongrass). These compounds provide a wealth of opportunity for the improvement of human health by decreasing the risk of developing cancer. However, the promise that a chemopreventive compound holds can only be realized if the compound has sufficient bioavailability to exert its pharmacological effect. For orally administered compounds (such as chemopreventive compounds from foods), intestinal disposition will play a major role in their overall bioavailability. While current research on chemopreventive compounds focuses on their discovery and discerning their mechanism of action, studies on the bioavailability and mechanisms of absorption and metabolism have been relatively lacking. Research on the intestinal disposition (i.e., intestinal permeability and metabolism) of chemopreventive agents is particularly important. The issue of intestinal disposition and how it affects bioavailability is critical to the in vivo biological activity of any orally ingested dietary compound. Sulforaphane (SFN), an isothiocyanate chemopreventive agent found in cruciferous vegetables, is known to modulate the expression of a membrane transport protein and several metabolizing enzymes that are present in the intestine. Therefore, to enhance our understanding of the oral bioavailability and mechanisms of absorption and metabolism of chemopreventive compounds, we propose to determine (A) the intestinal disposition of SFN and (B) how SFN's effects on gene/protein expression in the intestine (potential biomarkers of cancer chemoprevention activity) can affect the bioavailability of xenobiotics, including SFN itself. Our hypothesis is that dietary chemopreventive compounds such as SFN can affect their own bioavailability and the bioavailability of other xenobiotics by modulating the expression of Phase II detoxifying enzymes and membrane transporters in the Intestine. To test this hypothesis, the following Specific Aims will be addressed in this proposal: Specific Aim 1: Determine the intestinal disposition of SFN in the rat using single-pass intestinal perfusion technique (SPIP) with and without mesenteric vein cannulation and diffusion chamber studies. Specific Aim 2: Determine the effects of SFN on the gene expression of several Phase II detoxifying enzymes that are potential biomarkers of chemopreventive effects as well as membrane transporters that could affect intestinal disposition of xenobiotics and correlate the effects to the permeability of SFN. Results from these studies will enhance our understanding of the bioavailability and mechanisms of absorption and metabolism of the dietary chemopreventive compound, SFN. The issues of intestinal disposition and bioavailability ultimately determine the in vivo effects of chemopreventive compounds and understanding the underlying mechanisms will lead to improved cancer prevention modalities.