Structure-nephrotoxicity relationships for meta-substituted N-phenylsuccinimides.
The N-phenylsuccinimides are being evaluated as experimental agricultural fungicides. The purpose of this study was to examine the relationship between the electron withdrawing or electron donating properties of phenyl ring substituents on meta-substituted N-phenylsuccinimide (NPS) derivatives and the nephrotoxic potential of the corresponding fungicides. Male Fischer 344 rats were administered a single intraperitoneal injection of a succinimide (0.4 or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg), and renal function monitored at 24 and 48 hr. Non-halogen-substituted NPS derivatives produced little evidence of nephrotoxicity at the doses used in this study. Among the meta-halogen derivatives of NPS, N-(3-chlorophenyl)succinimide (NCPS) was the most nephrotoxic. NCPS-induced nephrotoxicity was characterized by diuresis, proteinuria, hematuria, elevated blood urea nitrogen (BUN) concentration, decreased organic ion accumulation and proximal tubular necrosis. However, all renal effects produced by NCPS were mild to moderate. These results suggest that the electron withdrawing or donating property of a functional group is not a good predictor of the nephrotoxic potential for the corresponding fungicide. In addition, lipophilicity did not correlate with nephrotoxic potential for the meta-substituted NPS derivatives evaluated in this study.
D000818:Animals; D001806:Blood Urea Nitrogen; D004231:Diuresis / Q000187:drug effects; D004583:Electrons; D005659:Fungicides, Industrial / Q000633:toxicity*; D006417:Hematuria / Q000139:chemically induced; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000633:toxicity*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
D005659:Fungicides, Industrial; D013388:Succinimides; D013757:Tetraethylammonium Compounds; D019789:Tetraethylammonium; D010130:p-Aminohippuric Acid