Dietary fat modulated metabolic fate of fluoranthene

性状（由申请方提供）：通过饮食摄入时，许多疏水和亲脂性环境毒物通过被动扩散通过胃肠道吸收。这些化学品在肠道通道中的吸收程度以及影响其吸收的因素对于确定通过饮食摄入的化学品的吸收效率至关重要。在这项研究中，我们将测试的假设，即在饮食中的脂质负荷调节荧蒽（弗拉;有毒的，和致突变的多环芳烃化合物）的吸收，导致弗拉转化为它的活性代谢物在体内和DNA加合物形成的程度。我们提出以下三个具体目标来检验假设：i）研究口服弗拉的生物利用度、代谢和毒代动力学以及不同浓度膳食脂肪和不同剂量下反应性代谢物的命运，ii）使用基于生理学的药代动力学模型估计弗拉的处置，和iii）研究膳食脂肪对靶组织中FLA-DNA加合物的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个全面的图片的命运和后果的致癌化学品摄入通过富含脂质的饮食。这些研究的结果具有重要意义，因为它们有助于更好地了解饮食调节对体内弗拉处置所起的作用以及生物可利用剂量导致致癌性的机制。

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.