Nephrotoxic and hepatotoxic potential of imidazolidinedione-, oxazolidinedione- and thiazolidinedione-containing analogues of N-(3,5-dichlorophenyl)succinimide (NDPS) in Fischer 344 rats.
Nephrotoxicity of the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) in rats is believed to involve metabolism on the succinimide ring. To further investigate this hypothesis, we synthesized and tested the following NDPS analogues, which contain other cyclic imide rings and may therefore be metabolized differently than NDPS: 3-(3,5-dichlorophenyl)-2,4-oxazolidinedione (DCPO), 3-(3,5-dichlorophenyl)-2,4-imidazolidinedione (DCPI), 3-(3,5-dichlorophenyl)-1-methyl-2,4-imidazolidinedione (DCPM) and 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT). Male Fischer 344 rats were administered DCPO, DCPI, DCPM, DCPT (0.6 or 1.0 mmol/kg, i.p. in corn oil), NDPS (0.6 mmol/kg, i.p. in corn oil) or corn oil (4 ml/kg). As evidenced by diuresis, proteinuria, elevated blood urea nitrogen levels, increased kidney weights and proximal tubular damage, NDPS produced severe nephrotoxicity in the rats. In contrast, DCPO, DCPI, DCPM and DCPT were mild nephrotoxicants. None of the compounds elevated serum alanine transferase activity or liver weights in the rats, however DCPT produced centrilobular necrosis. These experiments confirm that NDPS-induced nephrotoxicity is critically dependent on the presence of the succinimide ring. Furthermore, replacement of the succinimide ring with a thiazolidinedione ring produced a more pronounced effect on the liver than on the kidney. Liver damage has been reported in type II diabetic patients taking troglitazone, rosiglitazone and pioglitazone. Since these compounds also contain a thiazolidinedione ring, DCPT may be useful for investigating the role of this structural feature in hepatotoxicity.
Kennedy
Erica L
EL
Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 South Forty-Third Street, Philadelphia, PA 19104-4495, USA.
Tchao
Ruy
R
Harvison
Peter J
PJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001806:Blood Urea Nitrogen; D056486:Chemical and Drug Induced Liver Injury; D005659:Fungicides, Industrial / Q000633:toxicity*; D007093:Imidazoles / Q000138:chemical synthesis / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D010080:Oxazoles / Q000138:chemical synthesis / Q000633:toxicity*; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344; D013388:Succinimides / Q000633:toxicity*; D013844:Thiazoles / Q000138:chemical synthesis / Q000633:toxicity*
D001786:Blood Glucose; D005659:Fungicides, Industrial; D007093:Imidazoles; D010080:Oxazoles; D013388:Succinimides; D013844:Thiazoles; C007352:N-(3,5-dichlorophenyl)succinimide; D000410:Alanine Transaminase