Ak. Nyarko et al., CYTOCHROME P450-MEDIATED METABOLISM AND NEPHROTOXICITY OF N-(3,5-DICHLOROPHENYL)SUCCINIMIDE IN FISCHER-344 RATS, Fundamental and applied toxicology, 37(2), 1997, pp. 117-124
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.