Effect of microsomal enzyme activity modulation on N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity.
N-(3,5-Dichlorophenyl)succinimide (NDPS) is an experimental agricultural fungicide which has been shown to be a selective nephrotoxin. The purpose of this study was to determine if a NDPS metabolite contributes to acute NDPS-induced nephrotoxicity. Male Sprague-Dawley or Fischer 344 rats were pretreated with a microsomal enzyme inducer [phenobarbital (PB) or 3-methylcholanthrene (3-MC)] or inhibitor [cobalt chloride (CoCl2) or piperonyl butoxide (PIBX)] followed by a single intraperitoneal injection of NDPS (0.2, 0.4 or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg). Renal function was monitored at 24 and 48 h. CoCl2 or PIBX pretreatment reduced NDPS-induced diuresis, proteinuria and hematuria, and reduced the increases seen in the blood urea nitrogen (BUN) concentration and kidney weight. NDPS-induced decreases in organic ion accumulation were not markedly altered by CoCl2 or PIBX pretreatment. PB pretreatment enhanced all NDPS- (0.2 mmol/kg) induced renal effects, while 3-MC pretreatment protected against NDPS-induced diuresis, proteinuria, hematuria, and increases in the BUN concentration observed in both rat strains. Kidney weight and organic ion uptake changes were not substantially different between NDPS-treated rats with or without 3-MC pretreatment. It was concluded that a metabolite(s) contributes to or is responsible for acute NDPS-induced nephrotoxicity and that at least 1 toxic metabolite might be of extrarenal origin.
D000818:Animals; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013388:Succinimides / Q000378:metabolism / Q000633:toxicity*
D013388:Succinimides; C007352:N-(3,5-dichlorophenyl)succinimide; D008748:Methylcholanthrene; D010882:Piperonyl Butoxide; D010634:Phenobarbital