Role of stereochemistry in N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) nephrotoxicity.
The nephrotoxicity induced by the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is mediated through oxidative metabolites of NDPS. Oxidation of the succinimide ring in NDPS yields the nephrotoxic metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and its hydrolysis product N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The oxidation 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-NDHSA are possible. The purpose of this study was to begin to explore the importance of the stereochemical orientation at the asymmetric carbon atom for the nephrotoxicity induced by NDPS metabolites. Male Fischer 344 rats were 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 monitored 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 both post-treatment days, increased proteinuria, glucosuria, and increased kidney weight and BUN concentration. No evidence of hepatotoxicity was obtained in any treated group. Thus, the S-isomer of 2-NDHSA is a more potent nephrotoxicant than the R-isomer, and stereochemistry may play a role in NDPS metabolite-induced nephrotoxicity.
Rankin
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Department of Pharmacology, Joan C. Edwards School of Medicine, Marshall University, 1542 Spring Valley Drive, Huntington, WV 25704-9388, USA. rankin@marshall.edu
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Anestis
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Ball
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Valentovic
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Brown
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Hubbard
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D000818:Animals; D001806:Blood Urea Nitrogen; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005659:Fungicides, Industrial / Q000737:chemistry / Q000633:toxicity*; D006029:Glycosuria / Q000139:chemically induced; D007202:Indicators and Reagents; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008968:Molecular Conformation; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013386:Succinates / Q000737:chemistry / Q000633:toxicity*; D014563:Urodynamics / Q000187:drug effects
D005659:Fungicides, Industrial; D007202:Indicators and Reagents; D013386:Succinates; C070595:N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid