The role of glucuronidation in N-(3,5-dichlorophenyl)succinimide (NDPS) nephrotoxicity: nephrotoxic potential of NDPS and NDPS metabolites in Gunn, Wistar, and Fischer 344 rats.

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is an acute nephrotoxicant in rats. Although the mechanism of NDPS nephrotoxicity is not clear, our previous studies have strongly suggested that glucuronide conjugation of NDPS metabolite(s) is an important biotransformation reaction leading to the ultimate nephrotoxicant metabolite(s) mediating NDPS nephrotoxicity. In this study, the nephrotoxic potential of NDPS and its nephrotoxicant metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA), was examined in Gunn rats, which contain a genetic deficiency in bilirubin uridine diphosphate-glucuronosyltransferase (UDPGT), to explore further the role of glucuronidation in NDPS nephrotoxicity. The nephrotoxic potential of NDPS, NDHS, and NDHSA was also examined in Wistar rats, the parent strain for Gunn rats and which generally have normal UDPGT activity. Comparisons were then made with the nephrotoxicity induced by these compounds in Fischer 344 (F344) rats. Age-matched male F344, homozygous (j/j) Gunn, and Wistar rats were used. Rats (four to eight rats/group) of each strain were administered NDPS (0.4 mmol/kg ip), NDHS (0.1 or 0.2 mmol/kg ip), NDHSA (0.1 mmol/kg ip), or vehicle, and renal effects were monitored functionally and morphologically for 48 h. NDPS and its nephrotoxicant metabolites, NDHS and NDHSA, were much weaker nephrotoxicants in Gunn rats than in F344 rats, while Wistar rats were susceptible to the nephrotoxicity induced by NDPS, NDHS, or NDHSA. These results suggest that the lack of NDPS nephrotoxicity observed in Gunn rats is due to the deficiency in UDPGT in this strain rather than the parent Wistar strain being inherently nonresponsive to NDPS nephrotoxicity. Therefore, it appears that glucuronide metabolite(s) of NDHS and/or NDHSA contribute(s) to NDPS nephrotoxicity, although the exact nature of the nephrotoxicant glucuronide metabolite(s) of NDPS remains to be determined. Copyright 1999 Academic Press.