Effect of three n-acetylamino acids on N-(3,5-dichlorophenyl)succinimide (NDPS) and ndps metabolite nephrotoxicity in Fischer 344 rats.

Abstract

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.

• Authors: Gary O Rankin, Suk K Hong, Dianne K Anestis, Travis T Henderson, John G Ball, Monica A Valentovic, Patrick I Brown
• Journal: Journal of toxicology and environmental health. Part A (J Toxicol Environ Health A) Vol. 65 Issue 7 Pg. 539-56 (Apr 12 2002) ISSN: 1528-7394 [Print] England
• PMID: 11939711 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amino Acids
• Fungicides, Industrial
• Succinates
• Succinimides
• N-(3,5-dichlorophenyl)-2-hydroxysuccinimide
• N-acetylalanine
• Serotonin
• N,N-di-n-propylserotonin
• Serine
• N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid
• Alanine
• N-acetylserine
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Alanine (analogs & derivatives, pharmacology)
• Amino Acids (pharmacology)
• Animals
• Fungicides, Industrial (toxicity)
• Injections, Intraperitoneal
• Kidney (drug effects)
• Kidney Diseases (chemically induced)
• Kidney Function Tests
• Liver (drug effects)
• Male
• Rats
• Rats, Inbred F344
• Serine (analogs & derivatives, pharmacology)
• Serotonin (analogs & derivatives, toxicity)
• Succinates (toxicity)
• Succinimides (toxicity)