TRANSPORT OF PESTICIDES MEDIATED BY MRP1 AND MRP3

农药继续通过人类活动进入环境，并因其存在于我们所吃的食物中、流入水中以及在土壤和沉积物中持续存在而对健康构成威胁。要确定农药对人类和其他生物造成了多大的危害，必须查明它们在细胞内的积累和消除机制，因为细胞内的浓度直接影响其毒性。农药是如何从细胞中被清除并最终进入人体的，人们对其机制还不是很了解。一些膜结合的atp结合盒（ABC）转运体参与了它们的外排，但证据非常有限。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)，它们介导葡萄糖醛酸盐、谷胱甘肽和硫酸盐生理化合物和外源性配体的偶联物的消除，可能参与了细胞中农药的消除。我们建议调查19种农药，这些农药要么是目前使用的，要么是过去广泛使用的，并且在许多领域和基质中被常规检测为污染物。这些农药可以作为偶联物从生物体中清除，因此可能需要MRP1和/或MRP4来介导它们的外排。我们认为，MRP1和MRP3对农药的运输和消除会导致解毒，从而保护生物体免受农药的有害影响，但可能会改变生理化合物的正常运输。我们将研究MPR1和MPR3对农药的实际运输，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会竞争性地抑制和改变重要生理化合物的正常消除。

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.