ABSTRACT
The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) can induce marked nephrotoxicity in rats following a single intraperitoneal (ip) administration of 0.4mmol/kg or greater. Although NDPS induces direct renal proximal tubular toxicity, a role for renal vascular effects may also be present. The purpose of this study was to examine the possible role of vasoconstrictor leukotrienes in NDPS and NDPS metabolite nephrotoxicity. Male Fischer 344 rats (4 rats/group) were administered diethylcarbamazine (DEC; 250 or 500mg/kg, ip), an inhibitor of LTA(4) synthesis, 1h before NDPS (0.4mmol/kg, ip), N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.1, 0.2, or 0.4mmol/kg, ip), or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA, 0.1mmol/kg, ip) or vehicle. In a separate set of experiments, the LTD(4) receptor antagonist LY171883 (100mg/kg, po) was administered 0.5h before and again 6h after NDHS (0.1mmol/kg, ip) or 2-NDHSA (0.1mmol/kg, ip) or vehicle. Renal function was monitored for 48h post-NDPS or NDPS metabolite. DEC markedly reduced the nephrotoxicity induced by NDPS and its metabolites, while LY171883 treatments provided only partial attenuation of NDHS and 2-NDHSA nephrotoxicity. These results suggest that leukotrienes contribute to the mechanisms of NDPS nephrotoxicity.
Subject(s)
Fungicides, Industrial/toxicity , Kidney/drug effects , Leukotrienes/physiology , Succinimides/toxicity , Acetophenones/pharmacology , Animals , Diethylcarbamazine/pharmacology , Injections, Intraperitoneal , Kidney/pathology , Leukotriene A4/metabolism , Leukotriene A4/physiology , Leukotrienes/metabolism , Male , Rats , Rats, Inbred F344 , Receptors, Leukotriene/drug effects , Succinates/pharmacology , Succinimides/pharmacology , Tetrazoles/pharmacologyABSTRACT
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.
Subject(s)
Alanine/analogs & derivatives , Amino Acids/pharmacology , Fungicides, Industrial/toxicity , Kidney Diseases/chemically induced , Serine/analogs & derivatives , Serotonin/analogs & derivatives , Serotonin/toxicity , Acetylcysteine/pharmacology , Alanine/pharmacology , Animals , Injections, Intraperitoneal , Kidney/drug effects , Kidney Function Tests , Liver/drug effects , Male , Rats , Rats, Inbred F344 , Serine/pharmacology , Succinates/toxicity , Succinimides/toxicityABSTRACT
Chloronitrobenzenes are important chemical intermediates in the manufacture of industrial, agricultural and pharmaceutical agents. Toxicity induced by the various chloronitrobenzene isomers in vivo includes hematotoxicity, immunotoxicity, hepatotoxicity and nephrotoxicity. The purpose of the study was to determine the direct nephrotoxic effects of nitrobenzene and ten chlorinated nitrobenzene derivatives using renal cortical slices as the in vitro model. Renal cortical slices were prepared from kidneys of untreated, male Fischer 344 rats and incubated with nitrobenzene (1.0-5.0 mM), a chloronitrobenzene (0.5-5.0 mM) or vehicle for 2 h. At the end of the 2 h incubation, tissue gluconeogenesis capacity (pyruvate-stimulated gluconeogenesis) and lactate dehydrogenase (LDH) release were determined as measures of cellular function and cytotoxicity. Based on decreased pyruvate-stimulated gluconeogenesis and increased LDH release, the order of decreasing nephrotoxic potential was trichloronitrobenzenes>dichloronitrobenzenes>monochloronitrobenzenes>nitrobenzene. Among the mono- and dichloronitrobenzenes, 1-chloro-3-nitrobenzene and 3,4-dichloronitrobenzene were the most potent nephrotoxicants, while the two trichloronitrobenzenes tested exhibited similar nephrotoxic potentials. These results demonstrate that chloronitrobenzenes are directly nephrotoxic in vitro and that increasing the number of chloro groups increases the nephrotoxic potential of the resulting chloronitrobenzene derivative.
