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Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats. 2012

Gary O Rankin, and Suk K Hong, and Dianne K Anestis, and John G Ball, and Monica A Valentovic, and Vincent A Graffeo
Department of Pharmacology, Physiology & Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA. rankin@marshall.edu

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) can induce marked nephrotoxicity in rats following a single intraperitoneal (ip) administration of 0.4mmol/kg or greater. Although NDPS induces direct renal proximal tubular toxicity, a role for renal vascular effects may also be present. The purpose of this study was to examine the possible role of vasoconstrictor leukotrienes in NDPS and NDPS metabolite nephrotoxicity. Male Fischer 344 rats (4 rats/group) were administered diethylcarbamazine (DEC; 250 or 500mg/kg, ip), an inhibitor of LTA(4) synthesis, 1h before NDPS (0.4mmol/kg, ip), N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.1, 0.2, or 0.4mmol/kg, ip), or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA, 0.1mmol/kg, ip) or vehicle. In a separate set of experiments, the LTD(4) receptor antagonist LY171883 (100mg/kg, po) was administered 0.5h before and again 6h after NDHS (0.1mmol/kg, ip) or 2-NDHSA (0.1mmol/kg, ip) or vehicle. Renal function was monitored for 48h post-NDPS or NDPS metabolite. DEC markedly reduced the nephrotoxicity induced by NDPS and its metabolites, while LY171883 treatments provided only partial attenuation of NDHS and 2-NDHSA nephrotoxicity. These results suggest that leukotrienes contribute to the mechanisms of NDPS nephrotoxicity.

UI MeSH Term Description Entries
D007274 Injections, Intraperitoneal Forceful administration into the peritoneal cavity of liquid medication, nutrient, or other fluid through a hollow needle piercing the abdominal wall. Intraperitoneal Injections,Injection, Intraperitoneal,Intraperitoneal Injection
D007668 Kidney Body organ that filters blood for the secretion of URINE and that regulates ion concentrations. Kidneys
D008297 Male Males
D011916 Rats, Inbred F344 An inbred strain of rat that is used for general BIOMEDICAL RESEARCH purposes. Fischer Rats,Rats, Inbred CDF,Rats, Inbred Fischer 344,Rats, F344,Rats, Inbred Fisher 344,CDF Rat, Inbred,CDF Rats, Inbred,F344 Rat,F344 Rat, Inbred,F344 Rats,F344 Rats, Inbred,Inbred CDF Rat,Inbred CDF Rats,Inbred F344 Rat,Inbred F344 Rats,Rat, F344,Rat, Inbred CDF,Rat, Inbred F344,Rats, Fischer
D004049 Diethylcarbamazine An anthelmintic used primarily as the citrate in the treatment of filariasis, particularly infestations with Wucheria bancrofti or Loa loa. Carbamazine,Diethylcarbamazine Citrate,Diethylcarbamazine Citrate (1:1),Diethylcarbamazine Citrate (1:2),Diethylcarbamazine L-Tartrate (1:1),Diethylcarbamazine Maleate,Diethylcarbamazine Monohydrochloride,Diethylcarbamazine Phosphate (1:1),Hetrazan,Loxuran,Notezine,Citrate, Diethylcarbamazine,Maleate, Diethylcarbamazine,Monohydrochloride, Diethylcarbamazine
D005659 Fungicides, Industrial Chemicals that kill or inhibit the growth of fungi in agricultural applications, on wood, plastics, or other materials, in swimming pools, etc. Industrial Fungicides
D000098 Acetophenones Derivatives of the simplest aromatic ketone acetophenone (of general formula C6H5C(O)CH3).
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013386 Succinates Derivatives of SUCCINIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain a 1,4-carboxy terminated aliphatic structure. Succinic Acids,Acids, Succinic
D013388 Succinimides A subclass of IMIDES with the general structure of pyrrolidinedione. They are prepared by the distillation of ammonium succinate. They are sweet-tasting compounds that are used as chemical intermediates and plant growth stimulants. Butanimides,Pyrrolidinediones

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