Effect of sulfation substrates/inhibitors on N-(3,5-dichlorophenyl)succinimide nephrotoxocity in fischer 344 rats

Suk K. Hong, Dianne K. Anestis, Stephen Kennedy, Gary O. Rankin, Patrick I. Brown

Research output: Contribution to journalArticlepeer-review

Abstract

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-dichloro4-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.

Original languageEnglish (US)
Pages (from-to)47-62
Number of pages16
JournalJournal of Toxicology and Environmental Health - Part A
Volume57
Issue number1
DOIs
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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