TRANSPORT OF PESTICIDES MEDIATED BY MRP1 AND MRP3

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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.