Nephrotoxicity Induced by C- And N-Arylsuccinimides

Abstract

The succinimide ring is incorporated into hundreds of compounds that are widely used as agricultural, industrial, and pharmaceutical agents. Some succinimide derivatives that contain an aryl group on the ethylene bridge of the succinimide ring (C-arylsuccinimides) or on the nitrogen atom (N-arylsuccinimides) induce nephrotoxicity in humans and/or laboratory animals. Acute toxicity induced by this general class of compounds is typically characterized as polyuric renal failure, while chronic nephrotoxicity is seen as chronic interstitial nephritis. In this review, the structure-nephrotoxicity relationships, biotransformation, and mechanisms of nephrotoxicity for the C- and N-arylsuccinimides are examined.

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

“…S-2-NDHSA (0.1 mmol/ kg) and S-NDHS (0.1 mmol/kg) both induced marked nephrotoxicity, although at 0.1 mmol/ kg S-2-NDHSA induced changes in protein excretion and BUN concentration (Rankin et al, 2001b) were more pronounced than observed in this study with S-NDHS. Part of this difference may be due to hydrolysis of S-NDHS to 3-NDHSA, a weaker nephrotoxicant species than 2-NDHSA (Rankin, 2004). However, the exact mechanisms for these modest differences in the magnitude of nephrotoxicity induced by S-NDHS and S-2-NDHSA remain to be determined with certainty.…”

“…Many previous reports support NSC as being a penultimate or ultimate nephrotoxicant metabolite of NDPS (Cui et al, 2005;Rankin, 2004). Since the comparison of nephrotoxic potential for R-and S-NSC was made in an in vitro renal system, the lack of stereoselective nephrotoxicity indicates that, at least one mechanism to explain the stereoselective nephrotoxicity observed in vivo with NDPS metabolites is extrarenal in origin.…”

Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats

“…NDPS induces marked acute nephrotoxicity in male rats at ip doses of 0.4 mmol/kg or greater (Rankin, 1982; 2004; Rankin et al, 1984; 1985). Acute NDPS nephrotoxicity is characterized as polyuric renal failure with marked proximal tubular necrosis (Rankin; 2004).…”

Transamination in the Metabolism of the Nephrotoxicant N-(3,5-Dichlorophenyl)succinimide in Rats

“…In subsequent testing, NDPS was shown to be nephrotoxic in male rats at doses Ն0.4 mmol/kg following acute administration (Rankin, 1982;Rankin et al, 1985). Although not widely used, NDPS remains on the market as an agricultural fungicide, and it has been studied extensively as a model compound for chemically induced kidney damage (Rankin, 2004).…”

“…In subsequent testing, NDPS was shown to be nephrotoxic in male rats at doses Ն0.4 mmol/kg following acute administration (Rankin, 1982;Rankin et al, 1985). Although not widely used, NDPS remains on the market as an agricultural fungicide, and it has been studied extensively as a model compound for chemically induced kidney damage (Rankin, 2004).Studies in rats have shown that NDPS is well absorbed, widely distributed (highest in kidney), and rapidly eliminated, mainly as metabolites in urine (Ohkawa et al, 1974;Griffin and Harvison, 1998). The major in vivo metabolites of NDPS are N- (3,5-dichlorophenyl)succinamic acid (NDPSA), N-(3,5-dichlorophenyl)-2-and 3-hydroxysuccinamic acids (2-and 3-NDHSA), and N-(3,5-dichlorophenyl)malonamic acid (Ohkawa et al, 1974;Griffin and Harvison, 1998).…”