Cytochrome P450-mediated metabolism and nephrotoxicity of N-(3,5-dichlorophenyl)succinimide in fischer 344 rats

Abstract

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is nephrotoxic in rats. Previous studies have suggested that oxidative hepatic biotransformation is required for the induction of kidney damage. The experiments described in this paper were designed to further investigate 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), isoniazid (INH), 3-methylcholanthrene (3-MC), and phenobarbital (PB), or the P450 inhibitor 1-aminobenzotriazole (ABT). Control animals received vehicle only. NDPS metabolism was investigated using hepatocytes isolated from the various treatment groups. Separate experiments were also conducted to evaluate the effects of these pretreatments on NDPS-induced nephrotoxicity in rats. PB and ARO enhanced formation of the known nephrotoxic NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide, N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid, and N-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid, by the hepatocytes. In contrast, ABT inhibited formation of the nephrotoxic metabolites, whereas INH and 3-MC did not alter NDPS biotransformation. NDPS-induced renal damage was potentiated by pretreating the rats with PB or ARO and was attenuated by ABT. Compared with control animals, toxicity was unaffected by INH or 3-MC pretreatments. Thus, there was a correlation between pretreatments that induce P450-mediated NDPS metabolism and the effects that these compounds have on NDPS-induced nephrotoxicity. The data indicate that specific P450 isozymes metabolize NDPS to its hydroxylated products and suggest that these metabolites mediate the nephrotoxicity induced by NDPS.