Effect of three n-acetylamino acids on N-(3,5-dichlorophenyl)succinimide (NDPS) and ndps metabolite nephrotoxicity in Fischer 344 rats.
The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in mammals characterized as polyuric renal failure and proximal tubular necrosis. Recent studies have suggested that NDPS-induced nephrotoxicity may be mediated by metabolites arising from the nephrotoxic NDPS metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and/or N-(3,5-dichlorophenyl)-2-succinamic acid (2-NDHSA). The purpose of this study was to examine the effects of N-acetylcysteine (NAC), a nucleophilic agent, and two nonnucleophilic N-acetylamino acids, N-acetylserine (NAS) and N-acetylalanine (NAA), on NDPS and NDPS metabolite-induced nephrotoxicity. Male Fischer 344 rats (4-8/group) were administered intraperitoneally (ip) an N-acetylamino acid (1 mmol/kg) 2 h before an ip injection of NDPS (0.4 mmol/kg), NDHS (0.1 mmol/kg), 2-NDHSA (0.1 mmol/kg), or vehicle. Renal function was then monitored at 24 and 48 h. NAC pretreatment markedly attenuated NDPS-, NDHS-, and 2-NDHSA-mediated nephrotoxicity. The nonnucleophilic N-acetylamino acids (NAS, NAA) only partly reduced NDPS and NDHS nephrotoxicity, and they had little effect on 2-NDHSA nephrotoxicity. These results suggest that reactive NDPS metabolites may be formed from NDHS and 2-NDHSA and that nucleophilic substrates (e.g., NAC) may offer protection from NDPS-induced nephrotoxicity. However, mechanisms other than chemical neutralization of reactive NDPS metabolites may also be contributing to the attenuation of NDPS nephrotoxicity, since nonnucleophilic N-acetylamino acids (e.g., NAA) also provided some protection against NDPS and NDHS nephrotoxicity.
Rankin
Gary O
GO
Department of Pharmacology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia 25704-9388, USA. rankin@marshall.edu
Hong
Suk K
SK
Anestis
Dianne K
DK
Henderson
Travis T
TT
Ball
John G
JG
Valentovic
Monica A
MA
Brown
Patrick I
PI
D000111:Acetylcysteine / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D005659:Fungicides, Industrial / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced*; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012694:Serine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000633:toxicity*; D013386:Succinates / Q000633:toxicity; D013388:Succinimides / Q000633:toxicity
D000596:Amino Acids; D005659:Fungicides, Industrial; D013386:Succinates; D013388:Succinimides; C070526:N-(3,5-dichlorophenyl)-2-hydroxysuccinimide; C010530:N-acetylalanine; D012701:Serotonin; C055436:N,N-di-n-propylserotonin; D012694:Serine; C070595:N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid; D000409:Alanine; C012162:N-acetylserine; D000111:Acetylcysteine