Acute nephrotoxicity of N-phenyl and N-(monochlorophenyl) succinimides in Fischer 344 and Sprague-Dawley rats.
The experimental fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) has been shown to be nephrotoxic in Sprague-Dawley and Fischer 344 rats. The purpose of this study was to evaluate the role of the chlorine atoms in NDPS-induced nephropathy. Male Sprague-Dawley or Fischer 344 rats received a single intraperitoneal injection of a phenylsuccinimide (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg), and renal function was monitored at 24 h and 48 h. In Sprague-Dawley rats urine volume was increased by NDPS and N-(3-chlorophenyl)succinimide (3-NCPS) (0.4 and 1.0 mmol/kg) at 24 h but only by NDPS at 48 h. Accumulation of both p-aminohippurate (PAH) and tetraethylammonium (TEA) was decreased only by NDPS (1.0 mmol/kg) administration. N-(2-chlorophenyl)succinimide (2-NCPS) or N-(4-chlorophenyl) succinimide (4-NCPS) (1.0 mmol/kg) administration reduced only basal and lactate-stimulated PAH accumulation. Only NDPS increased blood urea nitrogen (BUN) concentration and kidney weight. In Fischer 344 rats results were similar to those obtained in Sprague-Dawley rats, except that 3-NCPS was the only monochlorophenylsuccinimide which produced a decrease in PAH accumulation by renal cortical slices. N-Phenylsuccinimide had little effect on any renal parameter studied in either rat strain. The order of increasing nephrotoxicity generally paralleled the increasing partition. coefficients of the compounds. These results indicate that reducing the chlorine substitution of NDPS produces compounds with reduced nephrotoxic potential. In addition, lipophilic character might be a predictor for the nephrotoxic potential of N-(halophenyl)succinimides in Sprague-Dawley and Fischer 344 rats.
D000818:Animals; D001806:Blood Urea Nitrogen; D002713:Chlorine / Q000633:toxicity; D004231:Diuresis / Q000187:drug effects; D005659:Fungicides, Industrial / Q000633:toxicity*; D007668:Kidney / Q000473:pathology; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000633:toxicity*; D019789:Tetraethylammonium / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
D005659:Fungicides, Industrial; D013388:Succinimides; C007352:N-(3,5-dichlorophenyl)succinimide; D002713:Chlorine; D019789:Tetraethylammonium; D010130:p-Aminohippuric Acid