Nephrotoxicity induced by the R - and S -enantiomers of N -(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and their sulfate conjugates in male Fischer 344 rats

• Published in: Toxicology (Amsterdam) 2007-10, Vol.240 (1), p.38-47
• Main Authors: Rankin, Gary O, Anestis, Dianne K, Valentovic, Monica A, Sun, Hang, Triest, William E
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Survival - drug effects; Cells, Cultured; Emergency; Fungicides; Kidney Cortex - cytology; Kidney Cortex - drug effects; Kidney Cortex - pathology; Kidney Diseases - chemically induced; Kidney Diseases - pathology; Kidney Diseases - urine; Kidney Function Tests; Male; Medical sciences; N-(3,5-Dichlorophenyl)-2-hydroxysuccinimide; Nephrotoxicity; Pesticides, fertilizers and other agrochemicals toxicology; Rats; Rats, Inbred F344; Stereoisomerism; Succinimides - chemistry; Succinimides - toxicity; Succinimides - urine; Sulfate conjugation; Sulfuric Acid Esters - chemistry; Sulfuric Acid Esters - toxicity; Sulfuric Acid Esters - urine; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2007.07.013

Abstract The agricultural fungicide N -(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity characterized as polyuric renal failure and mediated via metabolites arising from oxidation of the succinimide ring. Recent findings have suggested that the stereochemical nature of NDPS metabolites may be an important factor in NDPS metabolite-induced nephrotoxicity. The purpose of the present study was to determine the role of stereochemistry in the in vivo nephrotoxicity induced by R -(+)- and S -(−)- N -(3,5-dichlorophenyl)-2-hydroxysuccinimide ( R - and S -NDHS) and the in vitro nephrotoxicity induced by their enantiomeric sulfate conjugates, R -(−)- and S -(+)- N -(3,5-dichlorophenyl)-2-hydroxysuccinimide- O -sulfate ( R - and S -NSC). Male Fischer 344 rats (four rats/group) were administered intraperitoneally (i.p.) an enantiomer of NDHS (0.05, 0.1 or 0.2 mmol/kg) or vehicle, and renal function monitored for 48 h. R -NDHS (0.1 or 0.2 mmol/kg) had little effect on renal function. In contrast, S -NDHS (0.1 mmol/kg) induced marked nephrotoxicity. The nephrotoxic potential of R - and S -NSC (0.5, 0.75 or 1.0 mM) was determined using freshly isolated rat renal cortical cells (IRCC, 3–4 × 106 cells/ml). Cytotoxicity was determined by measuring the release of lactate dehydrogenase (LDH) at the end of a 1 h incubation period. The LDH release observed in these studies was similar between R - and S -NSC. These results indicate that stereochemistry is an important factor for NDPS metabolite nephrotoxicity and that the role of stereochemistry, at least for NSC, occurs at extra-renal sites.