Dietary fat modulated metabolic fate of fluoranthene

描述(申请人提供)：许多疏水性和亲脂性环境毒物通过饮食摄入后，被胃肠道被动扩散吸收。这些化学物质在肠道中的吸收程度和影响其吸收的因素对决定通过饮食摄入的化学物质的吸收效率至关重要。在这项研究中，我们将检验一种假设，即饮食中的脂质负荷调节荧蒽(Fla；一种有毒的、诱变的多环芳烃化合物)的吸收，导致Fla在体内转化为其反应性代谢物，并在DNA加合物形成的程度上。我们提出了以下三个具体目的来检验假设：1)研究口服FLA的生物利用度、代谢和毒代动力学以及不同浓度和不同剂量的FLA中反应性代谢物的去向；2)使用基于生理学的药代动力学模型估计FLA的分布；3)研究饮食脂肪对FLA-DNA加合物在靶组织中形成和持续的影响。我们的期望是，这项研究的结果将为我们提供一个全面的图景，了解通过高脂饮食摄入的致癌化学物质的命运和后果。这些研究的结果具有重要意义，因为它们有助于更好地理解饮食调节对FLA在体内的处置所起的作用，以及生物可用剂量促进致癌的机制。

DESCRIPTION (provided by applicant): Many hydrophobic and lipophilic environmental toxicants when consumed through diet are absorbed by passive diffusion across the gastrointestinal tract. The extent of absorption of these chemicals during gut passage and the factors governing their absorption are critical in determining the absorption efficiency of chemicals ingested through diet. In this research we will test the hypothesis that lipid load in the diet modulates fluoranthene (FLA; a toxic, and mutagenic polycyclic aromatic hydrocarbon compound) absorption resulting in conversion of FLA to its reactive metabolites in the body and in the extent of DNA-adduct formation. We propose the following three specific aims to test the hypothesis i) to study the bioavailability, metabolism and toxicokinetics of orally administered FLA and the fate of reactive metabolites in different concentrations of dietary fat and at different doses, ii) to estimate the disposition of FLA using a physiologically based pharmacokinetic model, and iii) to investigate the influence of dietary fat on formation and persistence of FLA-DNA adducts in target tissues. Our expectation is that findings from this research will provide us with a comprehensive picture of the fate and consequences of carcinogenic chemicals ingested through lipid rich diet. Results from these studies are significant in that they contribute to a greater understanding of the role played by dietary modulation on disposition of FLA in the body and the mechanisms by which bioavailable dose contributes to carcinogenicity.