Renal damage, metabolism and covalent binding following administration of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide (NDPS) to male Fischer 344 rats.
In vivo metabolism, nephrotoxicity and covalent binding to proteins were evaluated in male Fischer 344 rats that received [2,3-14C]-N-(3,5-dichlorophenyl)succinimide (14C-NDPS). Some animals were pretreated with the enzyme inducer phenobarbital (PB, 80 mg/kg per day, for 3 days, i.p. in saline) prior to receiving a non-nephrotoxic dose of 14C-NDPS (0.2 mmol/kg, i.p. in corn oil). Other rats were pretreated with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT, 100 mg/kg, 1 h prior to NDPS, i.p. in saline) before administration of a non-toxic or a toxic dose (0.2 or 0.6 mmol/kg, respectively, i.p. in corn oil) of 14C-NDPS. Non-pretreated animals received either dose of 14C-NDPS, but did not receive PB or ABT. All rats were sacrificed 6 h after administration of 14C-NDPS. Nephrotoxicity was monitored by measuring urine volume, urine protein concentrations, blood urea nitrogen levels, and kidney weights. The NDPS metabolic profile in tissue, blood, and urine was analyzed by HPLC. Covalent binding of 14C-NDPS-derived radioactivity to tissue proteins was also measured. Compared with non-pretreated rats, PB-pretreatment potentiated the toxicity of the non-toxic dose of 14C-NDPS. In contrast, ABT-pretreatment protected the rats against NDPS nephrotoxicity. The amount of N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA), an oxidative, nephrotoxic metabolite of NDPS, was elevated in kidney homogenates and urine by PB-pretreatment (0.2 mmol/mg NDPS). ABT pretreatment inhibited NDPS metabolism at both doses. Covalent binding of 14C-NDPS (0.2 mmol/kg)-derived radioactivity to renal and plasma proteins was higher in the PB-pretreated rats than in the non-pretreated animals. In contrast, ABT-pretreatment partially inhibited covalent binding at both doses of 14C-NDPS. Our results suggest that there is a relationship between oxidative metabolism of NDPS, covalent binding of an NDPS metabolite to renal proteins, and NDPS-induced nephrotoxicity in rats.
Henesey
Caroline M
CM
Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 South Forty-third Street, Philadelphia, PA 19104-4495, USA.
Harvison
Peter J
PJ
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005659:Fungicides, Industrial / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D013056:Spectrophotometry, Ultraviolet; D013388:Succinimides / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*
D005659:Fungicides, Industrial; D013388:Succinimides; C007352:N-(3,5-dichlorophenyl)succinimide