PMID: 9173678Apr 1, 1996Paper

In vitro metabolism of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide in the Fischer 344 rat and New Zealand white rabbit

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
R J GriffinPeter J Harvison

Abstract

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 ...Continue Reading

References

Dec 1, 1988·Toxicology and Applied Pharmacology·G O RankinP I Brown
Jan 1, 1985·Toxicology Letters·G O RankinP I Brown
Mar 1, 1968·Journal of Pharmaceutical Sciences·R B PaulssenT Higuchi
Feb 1, 1966·Journal of Pharmaceutical Sciences·A K HerdT Higuchi
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