Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats.
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.
Department of Pharmacology, Physiology & Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA. rankin@marshall.edu
Gary O
GO
Rankin
Suk K
SK
Hong
Dianne K
DK
Anestis
John G
JG
Ball
Monica A
MA
Valentovic
Vincent A
VA
Graffeo
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D004049:Diethylcarbamazine / Q000494:pharmacology; D005659:Fungicides, Industrial / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D017572:Leukotriene A4 / Q000378:metabolism / Q000502:physiology; D015289:Leukotrienes / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D018077:Receptors, Leukotriene / Q000187:drug effects; D013386:Succinates / Q000494:pharmacology; D013388:Succinimides / Q000494:pharmacology / Q000633:toxicity*; D013777:Tetrazoles / Q000494:pharmacology
D000098:Acetophenones; D005659:Fungicides, Industrial; D017572:Leukotriene A4; D015289:Leukotrienes; D018077:Receptors, Leukotriene; D013386:Succinates; D013388:Succinimides; D013777:Tetrazoles; C070526:N-(3,5-dichlorophenyl)-2-hydroxysuccinimide; C007352:N-(3,5-dichlorophenyl)succinimide; C070595:N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid; C044660:LY 171883; C083169:leukotriene D4 receptor; D004049:Diethylcarbamazine