Renal and hepatic toxicity of N-arylsuccinimides in Fischer 344 rats

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.