Aniline and its ring chlorinated derivatives produce a spectrum of toxicities which include hematotoxicity (methemoglobinemia, hemolytic anemia), nephrotoxicity (oliguria, hematuria, tubular necrosis) and to a lesser extent, hepatotoxicity. The proposed studies will investigate (a) the structural requirements for chloroaniline-induced nephropathy, (b) the role of metabolites in chloroaniline, organ-directed damage, and (c) some potential mechanisms and cellular targets of the chloroanilines. Nephrotoxicity will be monitored in both acute and subacute structural comparative studies by measuring a variety of urinary excretion patterns (volume, content, pH, osmolality), in vitro accumulation of organic ions by renal cortical slices, kidney weight, blood urea nitrogen (BUN) concentration and histology (light and electron microscopy). The direct toxic effects of chloroanilines to kidney will be examined using renal cortical slices and isolated renal epithelial cells. The role of toxic metabolites will be investigated using enzyme induction and inhibition studies, glutathione depletion studies, quantitation of covalent binding of chloroanilines to renal and hepatic proteins, molecular modification of chloroanilines, examination of the nephrotoxic potential of metabolites and determining the role of renal metabolism in chloroaniline-induced nephropathy. In addition, the temporal aspects of chloroaniline induced nephropathy, the renal accumulation (gross and subcellular) of these compounds and the role of free radicals in chloroaniline-induced organ damage will be examined. Also, the possibility that renal mitochondria are the cellular targets for chloroanilines will be explored. Lastly, changes in renal blood flow, cardiovascular function or hematological parameters will be examined as a causative or contributing mechanism in chloroaniline- induced nephropathy. The results obtained in these studies will further our knowledge in the area of chemical-induced renal disease. Identification of the metabolites responsible for or contributing to chloroaniline-induced renal damage will give us a better understanding of the role of biotransformation in the toxicity produced by these important compounds. Future studies will attempt to more precisely define the cellular mechanisms of chloroaniline- induced renal toxicity and the nephrotoxic potential of related chemical species.
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