Effect of Organophoshate Exposure on Cholesteryl Ester Hydrolase

有机磷酸盐暴露对胆固醇酯水解酶的影响

基本信息

批准号：
7908563
负责人：
MATTHEW K ROSS
金额：
$ 7.15万
依托单位：
MISSISSIPPI STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-03 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7908563
关键词：
Active Sites Aftercare Age Agriculture Agrochemicals American Area Arterial Fatty Streak Arteries Atherosclerosis Bile fluid Buffers Carboxylic Ester Hydrolases Cardiology Cardiovascular Diseases Cause of Death Cell Line Cell Proliferation Cell-Free System Cells Chemistry Chlorpyrifos Cholesterol Cholesterol Esters Cholesterol Homeostasis Congestive Heart Failure Connective Tissue Coronary Arteriosclerosis Coronary artery Country Cultured Cells Data Databases Disease Dose Environmental Health Environmental Risk Factor Enzymes Excretory function Exposure to Family Florida Genbank Genes Goals Grant Heart High Density Lipoproteins Human Hydrolase Hydrolysis Hypertension Incidence Insecticides Laboratories Left Liver Low-Density Lipoproteins Metabolism Methyl Parathion Mississippi Modification Molecular Target Myocardial Ischemia O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate Organophosphates Outcome Paraoxon Parathion Patients Pesticides Pharmacological Treatment Play Population Prevalence Probability Process Proteins Reaction Recombinants Recording of previous events Regulation Research Research Project Grants Risk Risk Factors Role Serine Serum Severities Smooth Muscle Myocytes Southeastern United States Stroke Structure Students System Testing Toxic Environmental Substances Training Transport Process United States United States National Institutes of Health Universities Valerates Ventricular Work adduct base carboxylesterase environmental chemical environmental toxicology esterase extracellular human disease inhibitor/antagonist insight low socioeconomic status macrophage member monocyte mortality particle prevent response reverse cholesterol transport statistics suicide inhibitor theories toxic organophosphate insecticide exposure

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) in its various forms is the leading cause of death in the United States. Reverse cholesterol transport is a mechanism by which cholesterol present in atherosclerotic plaques within arterial walls is transported to the liver via high density lipoprotein particles for excretion in bile. Recent studies have suggested that human cholesteryl ester hydrolase (CEH), an enzyme that metabolizes cholesteryl esters, plays an important role in the regulation of reverse cholesterol transport. This enzyme is identical to the carboxylesterase CES1. Our long term goal is to understand the role that environmental toxicants such as agricultural chemicals play in human disease. Three commonly used organophosphate (OP) insecticides will be used in this proposed study. The hypothesis to be tested is that exposure to OP insecticides will inhibit the CEH/CES1-catalyzed metabolism of cholesteryl esters, which could therefore increase the risk of developing atherosclerosis. Three aims are proposed: (1) Determine the dose response curve for the oxons of chlorpyrifos, parathion, and methyl parathion that inhibit the cholesterol ester hydrolyzing activity of recombinant CEH/CES1 enzyme; (2) Determine the dose response curve for these same oxons with respect to inhibition of CEH/CES1 activity in a human monocyte/macrophage cell line (THP1); (3) Characterize the CEH/CES1 protein adducts formed after treatment of recombinant CEH/CES1 and THP1 cells with chlorpyrifos oxon. We will determine the potency of the active metabolites (oxons) of three environmentally relevant OP insecticides to inhibit CEH/CES1-catalyzed cholesteryl ester hydrolysis activity in a cell-free system and in cultured cells. Furthermore, we will identify the covalent adduct of the protein that inactivates enzyme function. Several environmental factors may increase the incidence of CVD in humans. The results from this study will provide preliminary insights into whether OP oxon metabolites can directly alter the structure-function of an enzyme involved in cholesterol metabolism, thus leading to an increased probability of a pathological outcome (i.e. atherosclerosis). These studies will determine if active metabolites (oxons) of three environmentally relevant organophosphate insecticides can interfere with cholesterol metabolism.

描述（由申请人提供）：各种形式的心血管疾病（CVD）是美国的主要原因。胆固醇反向转运是动脉壁内动脉粥样硬化斑块中存在的胆固醇通过高密度脂蛋白颗粒转运至肝脏并在胆汁中排泄的机制。最近的研究表明，人胆固醇酯水解酶（CEH）是一种代谢胆固醇酯的酶，在胆固醇反向转运的调节中发挥着重要作用。该酶与羧酸酯酶 CES1 相同。我们的长期目标是了解农业化学品等环境毒物在人类疾病中所起的作用。本研究将使用三种常用的有机磷（OP）杀虫剂。待检验的假设是，接触 OP 杀虫剂会抑制 CEH/CES1 催化的胆固醇酯代谢，因此可能增加发生动脉粥样硬化的风险。提出三个目标：（1）确定毒死蜱、对硫磷和甲基对硫磷的氧磷抑制重组CEH/CES1酶胆固醇酯水解活性的剂量反应曲线； (2) 确定这些相同的oxon在人单核细胞/巨噬细胞系（THP1）中抑制CEH/CES1活性的剂量反应曲线； (3)表征用毒死蜱处理重组CEH/CES1和THP1细胞后形成的CEH/CES1蛋白加合物。我们将确定三种与环境相关的 OP 杀虫剂的活性代谢物（oxon）在无细胞系统和培养细胞中抑制 CEH/CES1 催化的胆固醇酯水解活性的效力。此外，我们将鉴定使酶功能失活的蛋白质的共价加合物。一些环境因素可能会增加人类心血管疾病的发病率。这项研究的结果将提供初步的见解，了解 OP oxon 代谢物是否可以直接改变参与胆固醇代谢的酶的结构功能，从而导致病理结果（即动脉粥样硬化）的可能性增加。这些研究将确定三种与环境相关的有机磷杀虫剂的活性代谢物（oxon）是否会干扰胆固醇代谢。