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 iV-(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. © 1997 Sodtty of To iV-(3,5-Dichlorophenyl)succinimide (NDPS, Fig.

Acute and subchronic evaluation of Indigofera arrecta: absence of both toxicity and modulation of selected cytochrome P450 isozymes in ddY mice

“…Modulation of CYP isozymes could precipitate interaction of xenobiotics via their metabolism (Nyarko et al, 1997). However, unlike other drugs, xenobiotics and phytomedicines (Pratt and Taylor, 1990;Gyamfi and Aniya, 1998), CYP isozyme-mediated metabolism in vitro was not affected by I. arrecta.…”

“…Recent evidence indicates that phytomedicines also modulate CYP isozymes and glutathione transferase activities (Gyamfi and Aniya, 1998). These may precipitate interactions via metabolism and hence alter the duration of pharmacological effects of components in a multiple drug therapy (Pratt and Taylor, 1990) or increase chemical toxicity (Nyarko et al, 1997). Certain isozymes hydroxylate p-nitrophenol (PNP) or dealkylate alkoxyresorufins (Reinke and Moyer, 1985;Harris et al, 1993).…”

Evaluation of efficacy and safety of a herbal medicine used for the treatment of malaria

“…Such modulations may precipitate interactions with other drugs (Nyarko et al, 1997). The significant increase in EROD activity in only the female rats given the AM-1 suggests that ethoxyresorufin-related substances, including certain drugs and environmental chemicals may be rapidly metabolized in female rats exposed to the decoction.…”

“…Similarly, the decoction has not been evaluated for any potential interactions that may arise from its concurrent administration with other preparations. For example, certain phytomedicines modulate cytochrome P450 (CYP) isozymes activities (Gyamfi and Aniya, 1998) and these may precipitate interactions via metabolism and hence alter the duration of pharmacological effects of components in a multiple drug therapy (Pratt and Taylor, 1990) or increase toxicity of certain chemicals (Nyarko et al ., 1997). Some of these isozymes hydroxylate p-nitrophenol (PNP) or dealkylate alkoxyresorufins (Reinke and Moyer, 1985;Harris et al ., 1993).…”

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

“…Glucuronide/sulfate and glutathione-derived conjugates of 2-/3-NDHSA and NDPS/NDPSA, respectively, have also been reported (Cui et al, 2005). Both phase I and II metabolic pathways may be involved in the formation of a nephrotoxic species from NDPS (Rankin et al, 1987;Nyarko et al, 1997; Hong et al, 1999a,b;Cui et al, 2005). Using liquid chromatography-MS/MS (Cui et al, 2005), we tentatively identified two novel amino-derived metabolites of NDPS, N-(3,5-dichlorophenyl)-2-aminosuccinamic acid (2-NDASA) and its N-acetylated derivative (N-acetyl-2-NDASA).…”