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

Abstract

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) can induce marked nephrotoxicity in rats following a single intraperitoneal (ip) administration of 0.4 mmol/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 500 mg/kg, ip), an inhibitor of LTA4 synthesis, 1h before NDPS (0.4 mmol/kg, ip), N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.1, 0.2, or 0.4 mmol/kg, ip), or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA, 0.1 mmol/kg, ip) or vehicle. In a separate set of experiments, the LTD4 receptor antagonist LY171883 (100 mg/kg, po) was administered 0.5 h before and again 6 h after NDHS (0.1 mmol/kg, ip) or 2-NDHSA (0.1 mmol/kg, ip) or vehicle. Renal function was monitored for 48 h 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.

Leukotrienes and kidney diseases

“…The agricultural fungicide NDPS [ N -(3,5-dichlorophenyl)-succinimide] and its metabolites NDHS [ N -(3,5-dichlorophenyl)-2-hydroxysuccinimide] and 2-NDHSA [ N -(3,5-dichlorophenyl)-2-hydroxysuccinamic acid] were shown to be nephrotoxic. Inhibition of 5LO markedly reduced all aspects of their nephrotoxicity in rats [ 33 ]. Several chemotherapeutic and cytotoxic agents were recently shown to act by inducing LTC 4 .…”