NEPHROTOXICITY OF N-(3-BROMOPHENYL)-2-HYDROXYSUCCINIMIDE - ROLE OF HALOGEN GROUPS IN THE NEPHROTOXIC POTENTIAL OF N-(HALOPHENYL)SUCCINIMIDES

Among N-(halophenyl)succinimides, N-(3,5-dichlorophenyl)succinimide (N DPS) is a potent nephrotoxicant as well as an agricultural fungicide. Although two chloride groups on the phenyl ring are essential to induc e optimal nephrotoxicity, the role of halogen groups in NDPS nephrotox icity is not clear. In this study, N-(3-bromophenyl)-2-hydroxysuccinim ide (NBPHS) was prepared as a monohalophenyl derivative of N-(3,5-dich lorophenyl)-2-hydroxysuccinimide (NDHS), an oxidative and nephrotoxica nt metabolite of NDPS. The nephrotoxic potential of NBPHS was evaluate d in vivo and in vitro to determine the role of halogen groups in N-(h alophenyl)succinimide nephrotoxicity. Male Fischer 344 rats (four/grou p) were administered a single intraperitoneal (i.p.) injection of NBPH S (0.1, 0.4 or 0.8 mmol/kg) or vehicle (25% dimethyl sulfoxide in sesa me oil) and renal function monitored for 48 h. Administration of NBPHS (0.8 mmol/kg) induced nephrotoxicity, while very mild changes or no c hanges 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 inc reased 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 o n organic ion accumulation, pyruvate-stimulated gluconeogenesis, and l actate 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 or greater, respectiv ely. Renal gluconeogenesis was inhibited by NBPHS at 1 mM bath concent ration, while LDH leakage was not increased at NBPHS bath concentratio ns up to 1 mM. The results demonstrate that NBPHS is a mild nephrotoxi cant in vivo and in vitro, but does not have cytotoxic effects to rena l 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 pl ay an important role in the mechanism of NDPS nephrotoxicity following NDHS formation.