Interaction of Nutrient & Organochlorine Absorption

描述(申请人提供)：有机氯化合物(OCs)有毒，致癌，在环境中普遍存在。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、脑和其他器官和组织中。虽然口服摄取是OCS在动物和人类体内积累的第一步，但涉及从肠道吸收以及早期在血液和淋巴中转运的过程尚未得到很好的描述。我们提出的研究将阐明这些重要的吸收和运输步骤，以提供一个基本的框架，可以导致理解营养物质影响吸收过程的方式。在具体目标1中，我们将确定OCS与淋巴和门静脉血中载体的吸收和结合方式，以及这是否受饲喂的脂类的数量和类型的影响。我们证明，作为甘油三酯(TG)的一部分，乳糜粒中携带的标记六氯苯(HCB)从循环中清除的速度快于标记脂肪酸(FA)。为了解释这一发现，标记的HCB一定没有溶解在乳胶粒的甘油三酯脂核中。如果是，那么它从循环中的去除速度应该比标记的TG慢或充其量等于标记的TG。因此，在特定的目标2中，我们将确定标记的OCS通过蛋白质、磷脂和乳胶粒(CMS)传递到组织(特别是脂肪组织)的方式。我们还将确定六氯苯在乳胶粒及其接触到的任何膜(例如红细胞膜)之间的分配。最后，在具体目标3中，我们将确定血液中携带标记OC的载体(白蛋白、脂或脂蛋白)的相对重要性是否因体重减轻或体重增加(即身体脂肪的变化)而改变。这项拟议的研究很重要，因为OCS在健康和疾病中具有生物学和临床重要性，而且它们为OCS如何被携带和输送到身体的不同器官提供了相当大的新见解。

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.