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.