Interaction of Nutrient & Organochlorine Absorption

描述（由申请人提供）：有机氯化合物（OCs）是有毒的，致癌的，在环境中无处不在。口服摄入是许多OCs进入人体的主要途径。由于OCs及其许多代谢物的亲脂性，它们优先储存在脂肪组织中，但也存在于肝脏、大脑和其他器官和组织中。虽然口服摄入是OCs在动物和人体内积累的第一步，但从肠道吸收和早期在血液和淋巴中的运输所涉及的过程尚未得到很好的表征。我们提出的研究将阐明吸收和运输中的这些重要步骤，以提供一个基本框架，可以导致理解营养影响吸收过程的方式。在具体目标1中，我们将确定OCs在淋巴和门静脉血液中的吸收模式和与载体的关联，以及这是否受到所喂脂质数量和类型的影响。我们证明，乳糜微粒中携带的标记六氯苯（HCB）比作为甘油三酯（TG）一部分的标记脂肪酸（FA）更快地从循环中清除。为了解释这一发现，标记的HCB一定没有溶解在乳糜微粒的TG脂质核心中。如果是，那么它从循环中去除的速度应该更慢，或者充其量等于标记的TG。因此，在特异性目标2中，我们将确定通过蛋白质、磷脂和乳糜微粒（CMs）将标记的OCs输送到组织（特别是脂肪组织）的模式。我们还将确定hcb在乳糜微粒和它所接触的任何膜（如红细胞膜）之间的分配。最后，在特异性目标3中，我们将确定携带标记OC的载体（白蛋白、脂质或脂蛋白）在血液中的相对重要性是否会因体重减轻或体重增加而改变（即体脂的变化）。拟议的研究很重要，因为OCs在健康和疾病中的生物学和临床重要性，它们为OCs如何被携带和运送到身体的各个器官提供了相当多的新见解。

DESCRIPTION (provided by applicant): Organochlorine compounds (OCs) are toxic, carcinogenic, and ubiquitous in the environment. Oral ingestion is the principal route of entry into the human body for many OCs. Because of the lipophilicity of OCs and many of their metabolites, they are preferentially stored in adipose tissue, but are also found in liver, brain, and other organs and tissues. Although oral ingestion is the initial step in the accumulation of OCs in animals and humans, the processes involved in absorption from the intestine and early transport in blood and lymph are not well characterized. We propose studies that will shed light on these important steps in absorption and transport to provide a basic framework that can lead to understanding the ways that nutrients influence the absorption processes. In Specific Aim 1, we will determine the mode of absorption and association of OCs with carriers in lymph and the portal blood and whether this is affected by the amount and the type of lipid fed. We demonstrated that labeled hexachlorobenzene (HCB) carried in chylomicrons is cleared from the circulation faster than the labeled fatty acid (FA) as part of the triglyceride (TG). To explain this finding, the labeled HCB must not have been dissolved in the TG lipid core of the chylomicron. If it is, then its rate of removal from the circulation should be slower or at best equal to that of the labeled TG. Consequently, in Specific Aim 2, we will determine the mode of delivery of labeled OCs to the tissues (especially the adipose tissue) by proteins, phospholipids, and chylomicrons (CMs). We will also determine the partitioning of HCBs between chylomicrons and any membranes it comes in contact with e.g., red blood cell membrane. Lastly, in Specific Aim 3, we will determine if the relative importance of vehicle (albumin, lipid, or lipoprotein) carrying the labeled OC in blood is altered as a result of weight loss or weight gain (i.e. changes in body fat). The proposed research is important because of the biological and clinical importance of OCs in health and disease and they provide considerable new insights into how OCs are carried and delivered to the various organs in the body.