The kidney is particularly sensitive to a wide array of xenobiotic compounds because, during the process of excreting these agents from the body, they frequently accumulate in renal cells. The ensuing compromise of renal function represents a major problem for workers exposed to certain environmental toxins, and to patients treated with agents that attack renal tissues. The proximal tubule is the principal site of toxicity of a wide variety of nephrotoxicants because it is the primary site of transport and secretion of organic molecules. In the present proposal we outline a series of studies that examine the role of the proximal tubule in the secretion of two specific groups of xenobiotic agents: (i) the cysteine conjugates and (ii) cisplatinum and related platinum derivatives. The cysteine conjugates are a broad class of environmental toxins that have been shown to damage the proximal tubule. Despite a number of studies implicating one or more transport pathways in the uptake and subsequent toxicity of these agents, it remains unclear which pathway or set of pathways provide the access to proximal cells required for the onset of toxicity. Cisplatinum is an antineoplastic agent widely used in the treatment of several cancers. Its use is complicated, however, by the development of nephrotoxicity. As with the cysteine conjugates, the onset of toxicity is believed to follow the uptake of cisplatinum into proximal tubular cells. Several studies have implicated organic ion transport pathways in this uptake, but evidence linking uptake to specific transport processes is limited. In this proposal we describe experiments designed to determine which renal transport processes are influenced by cysteine conjugates and cisplatinum, what the mechanisms of such interactions are, and the extent to which these molecules use specific transport pathways to actually enter renal cells. These studies will use radiotracer and electron-microprobe techniques to monitor transport of nephrotoxicants in experimental preparations representing several levels of biological organization, including suspensions of proximal tubules, single perfused and non-perfused renal tubules, and subcellular plasma membrane fractions. Using the information gained in the aforementioned experiments, we will determine the effect on the onset of toxicity of blocking, in a precisely defined manner, the mediated uptake of toxicants into proximal cells. The results of this study should assist in the development of protocols to ameliorate the toxic effects of these xenobiotic compounds.
