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.