Several succinimide derivatives produce renal damage (acute tubular necrosis, interstitial nephritis) in man and/or animals. The proposed study is a continuation of our currently funded project (AM31210) and will investigate (a) the structural requirements for nephrotoxicity, (b) the identity and site of formation of toxic metabolites, (c) potential cellular mechanisms of toxicity, and (d) the interactive potential of succinimides with nephrotoxic and hepatotoxic agents. Nephrotoxicity will be monitored in acute and subacute structural comparative studies by measuring a variety of urinary excretion parameters (volume, content, pH, osmolality), in vitro accumulation of organic ions by renal cortical slices and histology (light and electron microscopy). The identity and site of formation of metabolites will be examined using enzyme induction and inhibition studies, glutathione depletion studies, structural modification of nephrotoxic succinimides and by determining the nephrotoxic potential of known or suspected succinimide metabolites (in vivo, in vitro and isolated perfused kidney). If maleimide or other nephrotoxic metabolites are produced, they will be quantitated and identified using TLC, HPLC and GC/MS. Cellular mechanisms of toxicity will be examined in enzyme induction, calcium mediation of nephrotoxicity, lipid peroxidation, pro benecid modulation of nephrotoxicity and correlation of fungicidal activity with nephrotoxicity studies. The effect of various parameters (species, strain, sex and age) on succinimide-induced nephropathy also will be examined. The interactive potential of 3,5-NDPS with nephro- and hepatotoxins will be examined to determine if a nephrotoxic succinimide (3,5-NDPS) can alter the nephro- and/or hepatotoxic properties of selected toxins. In addition, the ability of these toxins to potentiate/reduce 3,5-NDPS-induced nephropathy also will be investigated. The results obtained from these studies will further our knowledge in the area of chemically-induced renal disease. The identification of maleimide metabolites would mean the discovery of a new class of toxic biotransformation products. Future studies will attempt to more precisely define the cellular mechanisms of succinimide-induced nephropathy, the nephrotoxic potential of related chemical species, and the mechanisms of toxic interactions between succinimides and other chemicals.
Showing the most recent 10 out of 44 publications
