Structure‐nephrotoxicity relationships for meta‐substituted N‐phenylsuccinimides

The role of aromaticity in the nephrotoxic potential of N-arylsuccinimides was studied in male Fischer 344 rats. Rats were administered a single intraperitoneal (i.p.) injection of an N-arylsuccinimide derivative (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg), and the renal function monitored at 24 and 48 h. The parent compound in this series, N-phenylsuccinimide (NPS), had previously been shown to induce only minimal renal effects, having no effect on urine volume, blood urea nitrogen concentration, kidney weight, p-aminohippurate accumulation or renal morphology. Only an increase in tetraethylammonium uptake has been observed following NPS administration to rats. These effects were not enhanced by reducing aromaticity (N-cyclohexylsuccinimide (NCS]. Compounds with increased aromaticity N-(1-naphthyl)succinimide (NNS), N-(1-anthracenyl)succinimide (1-NAS) and N-(9-anthracenyl)succinimide (9-NAS)--also only weakly affected renal function. However, NNS (1.0 mmol/kg) and, to a lesser degree, 9-NAS (1.0 mmol/kg) proved to be hepatotoxins. Liver damage was most pronounced near central vein regions of the lobule and least evident around periportal sites. Damaged liver tissue exhibited unusually large deposits of connective tissue and hypertrophied hepatocytes with numerous vacuoles in their cytoplasm. Therefore, derivatives of NPS with increased or decreased aromaticity relative to the parent compound do not exhibit the ability to induce moderate or marked nephrotoxicity. However, increasing aromaticity did produce the derivatives NNS and 9-NAS, which are hepatotoxins. These compounds represent the first members in this series of compounds to induce acute hepatotoxicity.

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Renal and hepatic toxicity of N‐arylsuccinimides in fischer 344 rats

Rankin

Carl

Hubbard

et al. 1989

J of Applied Toxicology

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Acute toxicity induced by 2‐aryl‐N‐methylsuccinimides

Rankin

Shih

Teets

et al. 1990

J of Applied Toxicology

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Phensuximide (PSX) is a 2-arylsuccinimide useful in the treatment of absence seizures. PSX is a mild urotoxicant and is structurally related to N-phenylsuccinimide (NPS) and its antifungal derivatives. Since substitution of the phenyl ring of NPS with chloro or tert-butyl groups can produce compounds with enhanced nephrotoxic potential, it was felt that similar substitutions on the phenyl ring of PSX also might produce derivatives with enhanced nephrotoxic potential. Three derivatives of PSX were prepared and tested: 2-(3-chlorophenyl)-N-methylsuccinimide (CPMS); 2-(4-tert-butylphenyl)-N-methylsuccinimide (BPMS) and 2-(3,5-dichlorophenyl)-N-methylsuccinimide (DPMS). In one set of experiments, male Fischer 344 rats were administered a single intraperitoneal (i.p.) injection of a succinimide (0.4 or 1.0 mmol kg-1) or vehicle (sesame oil, 2.5 ml kg-1) and renal function monitored at 24 and 48 h. Only minor changes in renal function were noted with the PSX derivatives. BPMS and DPMS (1.0 mmol kg-1) treatment induced mild renal tubular necrosis and thickening of the glomerular membranes. However, no significant morphological changes were noted in ureters, bladder or liver in any treatment group. In a second set of experiments, rats were pretreated with phenobarbital (75 mg kg-1 day-1, i.p., 3 days) followed by a single i.p. injection of DPMS (0.4 or 1.0 mmol kg-1) or DPMS vehicle. Renal function was monitored as before. Phenobarbital pretreatment did not markedly enhance the functional nephrotoxicity induced by DPMS (0.4 mmol), but tubular necrosis was greater than observed in non-phenobarbital-pretreated rats receiving DPMS (1.0 mmol kg-1). In addition, hepatotoxicity was observed as the appearance of numerous non-staining vacuoles in hypertrophied hepatocytes. In the phenobarbital plus DPMS (1.0 mmol kg-1) treatment group, all rats died by 48 h. Prior to death, rats exhibited increased proteinuria (+3), hematuria (+3) and blood urea nitrogen concentration. At 24 h, kidneys from rats treated with phenobarbital plus DPMS (1.0 mmol kg-1) exhibited extensive proximal tubular necrosis and numerous glomeruli with thickened membranes. Hepatotoxicity was more pronounced than with phenobarbital plus DPMS (0.4 mmol kg-1) at 48 h and urinary bladders had focal areas of erythrocytes pooling below the epithelial lining. These results demonstrate that although NPS and PSX are structural analogs, chemical substitutions that enhance the nephrotoxic potential of NPS do not have a similar effect on PSX. In addition, DPMS can induce urotoxicity in a manner similar to that observed for PSX and probably induces toxicity via one or more metabolites.

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Renal effects of N‐(3,5‐disubstitutedphenyl)‐succinimides in the fischer 344 rat

Rankin

Teets

Shih

et al. 1992

J of Applied Toxicology

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Previous studies have demonstrated the importance of substitution at the 3- and 5-positions of the phenyl ring in N-phenylsuccinimides for the production of nephrotoxicants in this series of compounds. The purpose of this study was to determine if the electronic nature of the 3,5-substituents is an important determinant for nephrotoxic potential. Male Fischer 344 rats (four rats per group) were administered a single intraperitoneal injection of a succinimide (0.4 or 1.0 mmol kg-1) or vehicle, and the renal function was monitored for 48 h. Only N-(3,5-dichlorophenyl)succinimide (0.4 or 1.0 mmol kg-1) induced marked changes in renal function. Urine volume, BUN concentration and proteinuria were increased following N-(3,5-dinitrophenyl)succinimide (1.0 mmol kg-1) treatment but other renal parameters and renal morphology were unchanged in this treatment group. These results indicate that the presence of halogen atoms at the 3- and 5-positions of the phenyl ring in N-phenylsuccinimides is more important for nephrotoxic potential than the presence of non-halogen substituents. The reason why halogen substitution is an important determinant for N-phenylsuccinimide nephrotoxicity is unknown.

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Structure‐nephrotoxicity relationships for meta‐substituted N‐phenylsuccinimides

Cited by 9 publications

References 12 publications

Renal and hepatic toxicity of N‐arylsuccinimides in fischer 344 rats

Renal and hepatic toxicity of N‐arylsuccinimides in fischer 344 rats

Acute toxicity induced by 2‐aryl‐N‐methylsuccinimides

Renal effects of N‐(3,5‐disubstitutedphenyl)‐succinimides in the fischer 344 rat

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