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The acute renal effects of the fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) were studied in male Sprague-Dawley rats. NDPS (50 mg/kg, i.p.) increased urine volume and decreased food intake and body weight at 24 h but not 48 h. No change in urine content or the accumulation by renal cortical slices of the organic anion p-aminohippurate (PAH) or the organic cation tetraethylammonium (TEA) was observed with 50 mg/kg NDPS when compared to control animals. Rats receiving 100 or 200 mg/kg NDPS (i.p.) exhibited increased urine volume, proteinuria, glucosuria, decreased food intake and body weight, increased BUN and decreased accumulation of PAH and TEA at both 24 h and 48 h. These effects were generally more pronounced at the 200 mg/kg dose level. Pair-fed control experiments demonstrated that renal effects were NDPS-induced and not related to daily food consumption. NO change in water intake was observed with any dose of NDPS used. The results demonstrate that NDPS alters renal function in a dose-dependent manner. In addition, NDPS (50 mg/kg) is capable of producing diuresis without apparent nephrotoxicity while doses of 100 mg/kg or more produce diuresis and nephrotoxicity.
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PMID:Nephrotoxicity following acute administration of N-(3,5-dichlorophenyl)succinimide in rats. 708 82

Although the addition of chloride groups to the phenyl ring of N-phenylsuccinimide (NPS) is known to enhance the nephrotoxic potential of NPS, the mechanism of this enhancement is unknown. One chlorinated NPS derivative, N-(3,5-dichlorophenyl)succinimide (NDPS), is a potent nephrotoxicant which induces marked proximal tubular necrosis at i.p. doses of 0.4 mmol/kg or greater. The purpose of this study was to compare the nephrotoxic potential of 2-hydroxy-N-phenylsuccinimide (HNPS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS), an oxidative and nephrotoxicant metabolite of NDPS, to determine the importance of the chloride groups for the nephrotoxic potential of NDHS. Male Fischer 344 rats (4/group) were administered a single i.p. injection of HNPS (1.0 or 1.5 mmol/kg), NDHS (0.1 mmol/kg) or vehicle (25% dimethyl sulfoxide in sesame oil), and renal function measured at 24 and 48 h. HNPS was a nonnephrotoxicant at both doses tested, while NDHS induced marked nephrotoxicity characterized by diuresis, increased proteinuria, glucosuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased organic ion accumulation by renal cortical slices and proximal tubular necrosis. In vitro, HNPS reduced p-aminohippurate (PAH) and tetraethylammonium (TEA) accumulation beginning at HNPS bath concentrations of 0.05 and 0.5 mM, respectively. The results of this study indicate that although HNPS has direct effects on renal function in vitro, HNPS is not a nephrotoxicant in vivo at doses up to 15 times the minimal nephrotoxicant dose of NDHS. Therefore, the chloro groups present on NDHS play an essential role in the nephrotoxic potential of NDHS and contribute to aspects of the nephrotoxic mechanism of NDPS beyond NDPS oxidation to form NDHS.
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PMID:Role of chloride groups in the nephrotoxic potential of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide, an oxidative metabolite of N-(3,5-dichlorophenyl)succinimide. 760 99

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is an established nephrotoxicant in male Fischer 344 rats at i.p. doses of > or = mmol/kg. Since gender differences often exist in the susceptibility to toxicants, the nephrotoxic potential of NDPS was examined in female Fischer 344 rats. Rats (4-5/group) were administered NDPS (0.1, 0.2, 0.4, or 1.0 mmol/kg, i.p.) or vehicle (sesame oil, 2.5 ml/kg) and renal function monitored for 48 h. At a dose of 0.1 mmol/kg, NDPS had no effect on renal function. However, administration of NDPS at a dose of 0.2 or 0.4 mmol/kg resulted in marked nephrotoxicity characterized by diuresis, increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased organic ion accumulation and proximal tubular necrosis. NDPS treatment of 1.0 mmol/kg resulted in oliguric renal failure rather than polyuric renal failure in 3 of 4 rats. Proximal tubular damage was observed primarily in the S3 segment of the proximal tubule in NDPS-treated female rats, while in male rats the S1 and S2 segments are the initial renal targets. These results demonstrate that female Fischer 344 rats are more susceptible to NDPS nephrotoxicity than male Fischer 344 rats and that the site of the renal lesion is gender dependent.
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PMID:Acute N-(3,5-dichlorophenyl)succinimide nephrotoxicity in female Fischer 344 rats. 816 Jan 97

We have previously reported that phenobarbital (PB) pretreatment enhances and piperonyl butoxide (PIBX) pretreatment or cobalt chloride (CoCl2) pretreatment decreases the nephrotoxicity induced by the model nephrotoxicant N-(3,5-dichlorophenyl)succinimide (NDPS) in the Fischer 344 rat. The objective of this study was to determine the effect of a microsomal enzyme inducer (PB) or microsomal enzyme inhibitor (PIBX or CoCl2) on a single intraperitoneal (i.p.) injection of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.05, 0.1 or 0.2 mmol/kg), a nephrotoxicant metabolite of NDPS, or vehicle (sesame oil, 2.5 ml/kg). Renal function was monitored at 24 and 48 h post-NDHS for PB pretreated rats and at 24 h only for PIBX and CoCl2 pretreated rats, due to lethality at 48 h in PIBX pretreated rats. PB pretreatment potentiated the renal toxicity induced by a non-toxic dose of NDHS (0.05 mmol/kg), inducing diuresis and elevated proteinuria, hematuria, glucosuria, blood urea nitrogen (BUN) concentration and kidney weight. PB pretreatment also enhanced some monitored renal effects of a toxic dose (0.1 mmol/kg) of NDHS, including reduced organic ion transport by renal cortical slices. PIBX and CoCl2 pretreatments did not markedly affect the increased kidney weight, proteinuria, glucosuria, BUN concentration or altered organic ion transport induced by NDHS (0.2 mmol/kg) treatment. We conclude that PB potentiates NDHS-induced nephrotoxicity via a mechanism not influenced by CoCl2 or PIBX.
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PMID:Effect of microsomal enzyme modulators on N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS)-induced nephrotoxicity in the Fischer 344 rat. 826 34

Among N-(halophenyl)succinimides. N-(3,5-dichlorophenyl)succinimide (NDPS) is a potent nephrotoxicant as well as an agricultural fungicide. Although two chloride groups on the phenyl ring are essential to induce optimal nephrotoxicity, the role of halogen groups in NDPS nephrotoxicity is not clear. In this study, N-(3-bromophenyl)-2-hydroxysuccinimide (NBPHS) was prepared as a monohalophenyl derivative of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS), an oxidative and nephrotoxicant metabolite of NDPS. The nephrotoxic potential of NBPHS was evaluated in vivo and in vitro to determine the role of halogen groups in N-(halophenyl)succinimide nephrotoxicity. Male Fischer 344 rats (four/group) were administered a single intraperitoneal (i.p.) injection of NBPHS (0.1, 0.4 or 0.8 mmol/kg) or vehicle (25% dimethyl sulfoxide in sesame oil) and renal function monitored for 48 h. Administration of NBPHS (0.8 mmol/kg) induced nephrotoxicity, while very mild changes or no changes in renal function were observed following administration of 0.4 mmol/kg or 0.1 mmol/kg of NBPHS, respectively. Nephrotoxicity induced by NBPHS (0.8 mmol/kg) was characterized by diuresis, transiently increased proteinuria, glucosuria and hematuria elevated kidney weight and reduced tetraethylammonium (TEA) uptake by renal cortical slices, and was not as marked as nephrotoxicity induced by NDHS (0.1 mmol/kg) or NDPS (0.4 mmol/kg). In the in vitro studies the effects of NBPHS on organic ion accumulation, pyruvate-stimulated gluconeogenesis, and lactate dehydrogenase (LDH) release were measured using renal cortical slices. NBPHS decreased p-aminohippurate (PAH) and TEA accumulation at NBPHS bath concentrations of 0.05 mM and 0.5 mM and 0.5 mM or greater, respectively. Renal gluconeogenesis was inhibited by NBPHS at 1 mM bath concentration, while LDH leakage was not increased at NBPHS bath concentrations up to 1 mM. The results demonstrate that NBPHS is a mild nephrotoxicant in vivo and in vitro, but does not have cytotoxic effects to renal tissues at the concentrations tested. From these results, it appears that halogen groups are essential to the nephrotoxic potential of N-(halophenyl)-2-hydroxysuccinimides or N-(halophenyl)succinimides and play an important role in the mechanism of NDPS nephrotoxicity following NDHS formation.
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PMID:Nephrotoxicity of N-(3-bromophenyl)-2-hydroxysuccinimide: role of halogen groups in the nephrotoxic potential of N-(halophenyl) succinimides. 865 56

N-(3,5-Dichlorophenyl)succinimide (NDPS) is an agricultural fungicide that induces nephrotoxicity as its major toxicity. NDPS is also a more potent nephrotoxicant in female than in male rats. The purpose of this study was to examine the nephrotoxic potential of the two NDPS metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) in age-matched male and female Fischer 344 rats to determine if gender differences exist for the nephrotoxicity induced by the two NDPS metabolites. Rats (4 per group) were administered a single intraperitoneal (ip) injection of NDHS or 2-NDHSA (0.025 or 0.05 mmol/kg) or vehicle, and renal function was monitored for 48 h. Neither compound induced significant nephrotoxicity in male rats at the doses tested. However, in female rats both metabolites induced marked nephrotoxicity at the 0.05 mmol/kg dose level, and treatment with 0.025 mmol/kg 2-NDHSA induced some changes in renal function (transient diuresis, transient proteinuria, decreased organic ion accumulation). Little effect on renal function was induced in females by treatment with 0.025 mmol/kg NDHS. At toxic levels in female rats, the renal lesions were located primarily in the S2 and S3 segments of the proximal tubule. These results indicate that, like the parent compound, gender differences exist in the nephrotoxic potential of NDHS and 2-NDHSA. The results also suggest that in females, as in males, NDPS nephrotoxicity is mediated via NDHS and/or 2-NDHSA. However, it is not clear if the ultimate nephrotoxicant species following NDPS exposure is different in males and females or if the same ultimate nephrotoxicant species is produced in both species but handled differently by male and female kidneys. Thus, further studies are needed to determine the exact nature of the ultimate nephrotoxicant species and the mechanisms of the observed gender differences.
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PMID:Gender differences in acute N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) nephrotoxicity in Fischer 344 rats. 972 83

N-(3,5-Dichlorophenyl)succinimide (NDPS) was originally developed as an agricultural fungicide. Previous work indicated that NDPS-induced renal damage in rats is metabolism-dependent and that hydroxylated metabolites might be involved in the nephrotoxic response. In this study, the disposition and nephrotoxicity of [14C]NDPS at two time points (3 and 24 hr) and three doses (0.2, 0.4, and 0.6 mmol/kg) were examined in male Fischer 344 rats. At 3 hr, only approximately 6.0% of the administered dose (0.6 mmol/kg) had been excreted. Elimination was nearly complete by 24 hr, except at the highest dose. Urinary elimination far exceeded fecal elimination at all doses. The urinary metabolites were identified as N-(3, 5-dichlorophenyl)succinamic acid, N-(3, 5-dichlorophenyl)-2-hydroxysuccinamic acid, N-(3, 5-dichlorophenyl)-3-hydroxysuccinamic acid, and N-(3, 5-dichlorophenyl)malonamic acid. N-(3, 5Dichlorophenyl)-3-hydroxysuccinamic acid had not been previously detected in vivo. The same metabolites were also detected in the feces, blood, liver, and kidneys of rats. In addition, two novel in vivo NDPS metabolites were detected in liver and kidney homogenates. These metabolites were tentatively identified as N-(3, 5-dichlorophenyl)-2-hydroxysuccinimide and N-(3, 5-dichloro-4-hydroxyphenyl)succinamic acid. Dose-dependent increases in blood urea nitrogen levels, diuresis, proteinuria, glucosuria, and covalent protein adducts correlated with increases in oxidative metabolism. Rapid NDPS metabolism could help explain the early onset of nephrotoxicity. These studies provide additional evidence for the importance of oxidative metabolism in NDPS-induced kidney damage.
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PMID:In vivo metabolism and disposition of the nephrotoxicant N-(3, 5-dichlorophenyl)succinimide in Fischer 344 rats. 973 70

Numerous structure-nephrotoxicity relationship studies from our laboratory have demonstrated that N-(3,5-dichlorophenyl)succinimide (NDPS) is one of the most potent nephrotoxicants among the N-arylsuccinimides. The purpose of this study was to extend our previous structure-nephrotoxicity relationship studies by examining the effect of addition of a fluoro verses a chloro group at the 4-phenyl position in NDPS. Male Fischer 344 rats (four rats/group) received a single intraperitoneal (i.p.) injection of N-(3,5-dichloro-4-fluorophenyl)succinimide (NDCFPS) or N-(3,4,5-trichlorophenyl)succinimide (NTCPS)(0.4 or 0.8 mmol/kg) or vehicle, and renal function monitored at 24 and 48 h. NDCFPS did not induce significant nephrotoxicity at either dose tested. In contrast, NTCPS (0.4 or 0.8 mmol/kg) induced marked nephrotoxicity characterized by diuresis, increased proteinuria, glucosuria, elevated kidney weight and increased blood urea nitrogen (BUN) concentration. NTCPS also induced marked proximal tubular necrosis at both doses tested. Neither NDCFPS nor NTCPS induced hepatotoxicity at either dose tested. The results of these experiments indicate that addition of a fluoro group at the 4-position on the phenyl ring of NDPS produces a nonnephrotoxicant NDPS derivative (NDCFPS), while addition of a chloro group at this site produces an NDPS derivative with similar nephrotoxic potential to NDPS. The mechanism for this differential effect between 4-halophenyl substitution is unclear, but may result from increased hydrolysis of the succinimide ring and/or increased clearance of N-arylsuccinimide metabolites when a fluoro group is added to the 4-position of the phenyl ring.
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PMID:Nephrotoxic potential of N-(3,5-dichloro-4-fluorophenyl)succinimide in Fischer 344 rats: comparison with N-(3,4,5-trichlorophenyl)succinimide. 1043 76

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity as its major toxicity in rats. Previous studies have shown that NDPS induces nephrotoxicity following oxidation of the succinimide ring to form N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and the hydrolysis product of NDHS, N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). Our recent work found that sodium sulfate potentiated NDPS nephrotoxicity, suggesting that sulfate conjugation of NDPS metabolites might be a bioactivation step mediating NDPS nephrotoxicity. The purpose of this study was to determine if sodium sulfate also potentiated the nephrotoxicity of the two nephrotoxic metabolites of NDPS and further to see if sodium sulfate potentiated NDHS and 2-NDHSA nephrotoxicity to the same degree. Male Fischer 344 rats (4-16 rats/group) received an intraperitoneal (ip) injection of sodium sulfate (10 mg/kg) 20 min before a non-nephrotoxic dose (0.05 mmol/kg, ip) of NDHS or 2-NDHSA, or vehicle (12.5% dimethyl sulfoxide in sesame oil). Renal function was then monitored over 48 h. Sodium sulfate pretreatment potentiated the renal effects of a non-nephrotoxic dose of NDHS and 2-NDHSA to induce nephrotoxicity. Nephrotoxicity was characterized by diuresis, increased proteinuria, elevated blood urea nitrogen (BUN) concentration, increased kidney weight and proximal tubular necrosis. Differences in the potentiation of NDHS and 2-NDHSA nephrotoxicity by sodium sulfate were also observed as NDHS nephrotoxicity was potentiated to a lesser degree than 2-NDHSA-induced nephrotoxicity. These results support the likelihood that one or more sulfate conjugate(s) of NDPS metabolites contribute to NDPS nephrotoxicity.
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PMID:Sodium sulfate potentiates N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) nephrotoxicity in the Fischer 344 rat. 1059 7

The nephrotoxicity induced by the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is mediated through oxidative metabolites of NDPS. Oxidation of the succinimide ring in NDPS yields the nephrotoxic metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and its hydrolysis product N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The oxidation of NDPS on the succinimide ring also introduces an asymmetric carbon atom into these NDPS metabolites, so that R- and S- enantiomers of NDHS and 2-NDHSA are possible. The purpose of this study was to begin to explore the importance of the stereochemical orientation at the asymmetric carbon atom for the nephrotoxicity induced by NDPS metabolites. Male Fischer 344 rats were administered a single intraperitoneal (ip) injection of R-(+)- or S-(-)-2-NDHSA (0.05, 0.1 or 2.0 mmol/kg) or vehicle, and renal function was monitored for 48 h. R-2-NDHSA (0.1 mmol/kg) administration had little effect on renal function. R-2-NDHSA (0.2 mmol/kg) treatment induced mild diuresis on day 1, increased proteinuria, and a small increase in blood urea nitrogen (BUN) concentration, but no change in kidney weight or glucosuria. S-2-NDHSA (0.1 mmol/kg) induced marked nephrotoxicity as evidenced by diuresis on both post-treatment days, increased proteinuria, glucosuria, and increased kidney weight and BUN concentration. No evidence of hepatotoxicity was obtained in any treated group. Thus, the S-isomer of 2-NDHSA is a more potent nephrotoxicant than the R-isomer, and stereochemistry may play a role in NDPS metabolite-induced nephrotoxicity.
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PMID:Role of stereochemistry in N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) nephrotoxicity. 1168 21


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