Role of stereochemistry in N-(3,5-dichlorophenyl)-2-hydroxysuccinamic (2-NDHSA) nephrotoxicity

The nephrotoxicity induced by the agricultural fungicide N-(3,5-dichlorophe nyl)succinimide (NDPS) is mediated through oxidative metabolites of NDPS. O xidation of the succinimide ring in NDPS yields the nephrotoxic metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and its hydrolysis prod uct N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The oxidatio n of NDPS on the succinimide ring also introduces an asymmetric carbon atom into these NDPS metabolites, so that R- and S- enantiomers of NDHS and 2-N DHSA are possible. The purpose of this study was to begin to explore the im portance of the stereochemical orientation at the asymmetric carbon atom fo r the nephrotoxicity induced by NDPS metabolites. Male Fischer 344 rats wer e administered a single intraperitoneal (ip) injection of R-( +)- or S-{-)- 2-NDHSA (0.05, 0.1 or 2.0 mmol/kg) or vehicle, and renal Function was monit ored for 48 h. R-2-NDHSA {0.1 mmol/kg) administration had little effect on renal function. R-2-NDHSA (0.2 mmol/kg) treatment induced mild diuresis on day 1, increased proteinuria, and a small increase in blood urea nitrogen ( BUN) concentration, but no change in kidney weight or glucosuria. S-2-NDHSA {0.1 mmol/kg) induced marked nephrotoxicity as evidenced by diuresis on bo th post-treatment days, increased proteinuria, glucosuria, and increased ki dney weight and BUN concentration. No evidence of hepatotoxicity was obtain ed in any treated group. Thus, the S-isomer of 2-NDHSA is a more potent nep hrotoxicant than the R-isomer, and stereochemistry may play a role in NDPS metabolite-induced nephrotoxicity. (C) 2001 Elsevier Science Ireland Ltd. A ll rights reserved.