Several succinimide derivatives have been shown to induce renal damage (acute tubular necrosis, interstitial fibrosis) or bladder damage (hemorrhagic cystitis) in man and/or animals. This proposal is designed to examine the mechanism(s) of N- and C-arylsuccinimide (NAS and CAS, respectively)-induced nephro- and urotoxicity. NAS nephrotoxicity is postulated to occur following conversion of NAS metabolites to conjugates in liver which accumulate in kidney to release N-arylmaleimides (NAM). The NAM then alkylate proximal tubular cell components (e.g., mitochondrial enzymes) to cause cell death. This hypothesis will be examined in studies which determine (a) the hepatic handling of NDPS, a prototypic NAS, (b) the generation of reactive NDPS metabolites in liver, blood and kidney (c) subcellular targets of NDPS metabolites, (d) the nephrotoxic potential of NDPS metabolite conjugates, their ability to release maleimides, and how they are transported in the kidney, (e) the ultimate nephrotoxic species following NDPS administration and (f) potential cellular mechanisms of toxicity. The importance of the 3,5- dihalo substitution for the expression of NAS nephrotoxicity and why GSH depletion attenuates NDPS nephrotoxicity also will be examined. Nephrotoxicity is monitored by measuring urinary excretion patterns, kidney weight, BUN concentration, in vitro accumulation of organic ions by renal cortical slices and histopathology (light and electron microscopy). Cellular toxicity will be measured in isolated epithelial cells and/or mitochondria by monitoring effects on cell calcium, ATP production, and oxygen consumption. CAS urotoxicity also is postulated to occur following the conversion of CAS to reactive species (i.e., maleimides). Using phensuximide (PSX), a prototypic CAS, the urotoxic mechanism will be studied by examining (a) which PSX metabolites are urotoxicants (b) the ability of MESNA to attenuate PSX urotoxicity (c) the role of stereochemistry in PSX-induced urotoxicity (d) if urotoxic metabolites arise from oxidation on the aryl or succinimide ring and (e) if maleimides are metabolites of PSX. Collectively, the results of these studies should add important, new knowledge about the nephro- and urotoxic species of succinimides, cellular targets of the toxicant species and potential mechanisms of nephro- and urotoxicity induced by the succinimides.
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