CYTOCHROME P450-MEDIATED METABOLISM AND NEPHROTOXICITY OF N-(3,5-DICHLOROPHENYL)SUCCINIMIDE IN FISCHER-344 RATS

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is nephrotoxic in rats. Previous studies have suggested that oxidative h epatic biotransformation is required for the induction of kidney damag e. The experiments described in this paper were designed to further in vestigate the relationship between NDPS metabolism and nephrotoxicity using various modulators of cytochrome P450 activity. Male Fischer 344 rats were pretreated with the P450 inducers Aroclor 1254 (ARO), isoni azid (INH), 3-methylcholanthrene (3-MC), and phenobarbital (PB), or th e P450 inhibitor 1-aminobenzotriazole (ABT). Control animals received vehicle only. NDPS metabolism was investigated using hepatocytes isola ted from the various treatment groups. Separate experiments were also conducted to evaluate the effects of these pretreatments on NDPS-induc ed nephrotoxicity in rats. PB and ARO enhanced formation of the known nephrotoxic NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinim ide, N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid, and N-(3,5-dichl orophenyl)-3-hydroxysuccinamic acid, by the hepatocytes. In contrast, ABT inhibited formation of the nephrotoxic metabolites, whereas INH an d 3-MC did not alter NDPS biotransformation. NDPS-induced renal damage was potentiated by pretreating the rats with PB or ARO and was attenu ated by ABT. Compared with control animals, toxicity was unaffected by INH or 3-MC pretreatments. Thus, there was a correlation between pret reatments that induce P450-mediated NDPS metabolism and the effects th at these compounds have on NDPS-induced nephrotoxicity. The data indic ate that specific P450 isozymes metabolize NDPS to its hydroxylated pr oducts and suggest that these metabolites mediate the nephrotoxicity i nduced by NDPS. (C) 1997 Society of Toxicology.