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 (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.
Hong
S K
SK
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25704-9388, USA.
Anestis
D K
DK
Hawco
N M
NM
Valentovic
M A
MA
Brown
P I
PI
Rankin
G O
GO
D000704:Analysis of Variance; D000818:Animals; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity*; D006029:Glycosuria / Q000139:chemically induced; D006417:Hematuria / Q000139:chemically induced; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced; D011773:Pyruvates / Q000633:toxicity; D019289:Pyruvic Acid; D051381:Rats; D011916:Rats, Inbred F344; D012715:Sesame Oil / Q000008:administration & dosage; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000652:urine; D010130:p-Aminohippuric Acid / Q000652:urine
D005659:Fungicides, Industrial; C099812:N-(3-bromophenyl)-2-hydroxysuccinimide; D011773:Pyruvates; D013388:Succinimides; D013757:Tetraethylammonium Compounds; C007352:N-(3,5-dichlorophenyl)succinimide; D019789:Tetraethylammonium; D012715:Sesame Oil; D019289:Pyruvic Acid; D007770:L-Lactate Dehydrogenase; D010130:p-Aminohippuric Acid; D004121:Dimethyl Sulfoxide