In vitro metabolism of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide in the Fischer 344 rat and New Zealand white rabbit.
1. The nephrotoxicant N-(3,5-dichlorophenyl)succinimide (NDPS) underwent nonenzymatic hydrolysis to N-(3,5-dichlorophenyl)succinamic acid (NDPSA) in buffer, rat liver and kidney homogenates, and rabbit liver homogenates. 2. In the presence of NADPH, rat liver homogenates converted NDPS to NDPSA and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). 3. Using liver homogenates from the phenobarbital (PB)-pretreated rat, 2-NDHSA production was increased 5-fold, and the metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid (3NDHSA) were also detected. Formation of these latter metabolites was suppressed by CO or omission of NADPH. No hydroxylated metabolites were detected when NDPSA was incubated with PB-induced rat liver homogenates. 4. Oxidative metabolites were not produced when NDPS was incubated with kidney homogenates from the control or PB-pretreated rat. 5. NDHS underwent rapid hydrolysis in buffer to yield 2-NDHSA and 3-NDHSA. 6. Rabbit liver homogenates converted NDPS to NDPSA, 3,5-dichloroaniline (DCA), and succinic acid (SA). Production of DCA and SA was inhibited by the amidase inhibitor bis-p-nitrophenyl phosphate. Oxidative metabolism did not occur in rabbit tissue. 7. These experiments demonstrate that a PB-inducible form of rat liver P450 converts NDPS to NDHS, which then undergoes hydrolysis to 2-NDHSA and 3-NDHSA. An alternative route of production for 2-NDHSA and 3-NDHSA, via hydroxylation of NDPSA, does not occur. In rabbit liver NDPS metabolism was primarily amidase-mediated.
Griffin
R I
RI
Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science, PA 19104-4495, USA.
Rutt
D B
DB
Henesey
C M
CM
Harvison
P J
PJ
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005659:Fungicides, Industrial / Q000378:metabolism* / Q000633:toxicity; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D013386:Succinates / Q000737:chemistry / Q000378:metabolism; D013388:Succinimides / Q000302:isolation & purification / Q000378:metabolism* / Q000633:toxicity; D015262:Xenobiotics / Q000378:metabolism
D005659:Fungicides, Industrial; D013386:Succinates; D013388:Succinimides; D015262:Xenobiotics; C007352:N-(3,5-dichlorophenyl)succinimide; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital