TRANSPORT OF PESTICIDES MEDIATED BY MRP1 AND MRP3

MRP1 和 MRP3 介导的农药运输

• 批准号: 6159373
• 负责人: LISA J BAIN
• 金额: $ 5.03万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-07 至 2001-08-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6159373
• 关键词: environmental contamination; environmental toxicology; pesticide biological effect; protein transport

Pesticides continue to enter the environment through human activities and pose a health risk by their presence in the food we eat, runoff into water, and persistence in soils and sediments. To determine how much of a problem pesticides pose to humans and other organisms, their accumulation and the mechanisms of elimination from cells must be ascertained, as the concentration within a cell directly effects its toxicity. The mechanisms by which pesticides are eliminated from cells and ultimately the body is not very well understood. Several membrane-bound ATP-binding cassette (ABC) transporters have been implicated in mediating their efflux, but the evidence is extremely limited. Two ABC transporters termed the human multidrug resistance-associated protein 1 (MRP1) and the human multidrug resistance-associated protein 3 (MRP3) that mediate the elimination of glucuronide, glutathione, and sulfate conjugates of physiological compounds and exogenous ligands, are probably involved in elimination of pesticides from cells. We propose to investigate nineteen pesticides that are either currently used, or have been used extensively in the past and are routinely detected as contaminants in many areas and matrices. These pesticides can be eliminated from the organism as conjugates, and therofore are likely to require MRP1 and/or MRP4 to mediate their efflux. We propose that transport and elimination of persticides by MRP1 and MRP3 results in detoxification, which protects the organism from their deleterious effects, but may alter the normal transport of physiological compounds. We will examine the actual transport of pesticides by MPR1 and MPR3, determine whether this elimination alters toxicity to cells that overexpress these proteins, and ascertain whether transport of pesticides competitively inhibits and alters the normal elimination of important physiological compounds.

农药继续通过人类活动进入环境，并通过我们所吃的食物中的存在、流入水中以及在土壤和沉积物中的持久存在而构成健康风险。 为了确定农药对人类和其他生物体造成的问题有多大，必须确定它们的积累和从细胞中消除的机制，因为细胞内的浓度直接影响其毒性。 农药从细胞和最终体内清除的机制尚不清楚。 几种膜结合 ATP 结合盒 (ABC) 转运蛋白参与介导其流出，但证据极其有限。 两种 ABC 转运蛋白被称为人类多药耐药相关蛋白 1 (MRP1) 和人类多药耐药相关蛋白 3 (MRP3)，它们介导生理化合物和外源配体的葡萄糖醛酸、谷胱甘肽和硫酸盐缀合物的消除，可能参与细胞中农药的消除。 我们建议对目前使用或过去广泛使用的 19 种农药进行调查，这些农药在许多地区和基质中经常被检测为污染物。 这些农药可以作为缀合物从生物体中消除，因此可能需要 MRP1 和/或 MRP4 来介导它们的流出。 我们认为，MRP1 和 MRP3 转运和消除杀虫剂会导致解毒，从而保护生物体免受有害影响，但可能会改变生理化合物的正常转运。 我们将检查MPR1和MPR3对农药的实际转运，确定这种消除是否会改变对过度表达这些蛋白质的细胞的毒性，并确定农药的运输是否竞争性地抑制和改变重要生理化合物的正常消除。