Dietary fat modulated metabolic fate of fluoranthene

描述（由申请人提供）：许多疏水和亲脂环境毒物通过饮食摄入时，通过胃肠道被动扩散被吸收。肠道对这些化学物质的吸收程度以及控制其吸收的因素对于确定通过饮食摄入的化学物质的吸收效率至关重要。在本研究中，我们将测试饮食中的脂质负荷调节氟蒽（FLA，一种有毒的、致突变的多环芳烃化合物）的吸收，从而导致FLA在体内转化为其活性代谢物，并在一定程度上形成dna加合物的假设。我们提出以下三个具体目标来验证这一假设：1)研究口服FLA的生物利用度、代谢和毒性动力学以及在不同浓度和不同剂量的膳食脂肪下反应性代谢物的命运；2)使用基于生理的药代动力学模型估计FLA的处理；3)研究膳食脂肪对靶组织中FLA- dna加合物形成和持久性的影响。我们的期望是，这项研究的结果将为我们提供一幅关于通过富含脂质饮食摄入致癌化学物质的命运和后果的全面图景。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在体内的配置所起的作用，以及生物可利用剂量对致癌性的作用机制。

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.