Effect of sulfation substrates/inhibitors on N-(3,5-dichlorophenyl)succinimide nephrotoxocity in Fischer 344 rats.
The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is an acute nephrotoxicant in rats. Our previous studies suggested that sulfate conjugation of NDPS metabolites might be a bioactivation step mediating NDPS nephrotoxicity. In this study, effects of substrates and/or inhibitors of sulfation on NDPS nephrotoxicity were examined to explore further the role of sulfation in NDPS nephrotoxicity. Male Fischer rats (4-8/group) were administered one of the following intraperitoneal (ip) pretreatment (dose, pretreatment time) prior to NDPS (0.6 mmol/kg) or NDPS vehicle (sesame oil, 2.5 ml/kg): (1) no pretreatment, (2) dehydroepiandrosterone (DHEA) (0.5 mmol/kg, 1 h), or (3) 2,6-dichloro-4-nitrophenol (DCNP) (0.04 mmol/kg, 1 h). Following NDPS or NDPS vehicle administration, renal function was monitored at 24 and 48 h. Pretreatment with DHEA, a typical substrate for and an inhibitor of hydroxysteroid (alcohol) sulfotransferase, resulted in marked protection against NDPS nephrotoxicity. A selective inhibitor of phenol sulfotransferase, DCNP, afforded little attenuation in NDPS nephrotoxicity. These results suggest that alcohol sulfate conjugates of NDPS metabolites, rather than phenolic sulfate conjugates, may be a penultimate or ultimate nephrotoxicant species mediating NDPS nephrotoxicity. The marked, but not complete, protection by DHEA also suggests that there are other metabolites or mechanisms responsible for NDPS nephrotoxicity.
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D001711:Biotransformation; D003687:Dehydroepiandrosterone / Q000627:therapeutic use*; D004435:Eating / Q000187:drug effects; D005659:Fungicides, Industrial / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D009596:Nitrophenols / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013388:Succinimides / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D013463:Sulfuric Acid Esters / Q000378:metabolism