Structure-nephrotoxicity relationships for para-substituted N-phenylsuccinimides in Sprague-Dawley and Fischer 344...

N-(3,5-Dichlorophenyl)succinimide (NDPS) has proven to be one of the most nephrotoxic compounds of a series of N-(halophenyl)succinimides. Previous studies in our laboratory have demonstrated that chlorine content and position on the phenyl ring are important determinants for NDPS-induced nephrotoxicity. The purpose of this study was to investigate the relationship between the electron donating or withdrawing nature of phenyl group substituents and the nephrotoxic potential of the corresponding fungicides. Rats were administered a para-substituted N-phenylsuccinimide (0.4 or 1.0 mmol/kg, i.p.) or sesame oil (2.5 ml/kg, i.p.), and renal function was monitored at 24 h and 48 h. In Sprague-Dawley rats, a clear nephrotoxicity was produced by NDPS. Weak nephrotoxicity was produced by N-(4-tert-butylphenyl)succinimide (NBPS). NDPS also was the most nephrotoxic compound in Fischer 344 rats, while weak nephrotoxicity was produced by NBPS. Lipophilic character (e.g. partition coefficient) did not correlate with acute nephrotoxicity in either rat strain. These results also indicate that there is a no correlation between the electronic nature of the phenyl substituents and resulting nephrotoxicity.