PMID: 8937861Nov 1, 1996Paper

Role of cytochrome P450 in oxazaphosphorine metabolism. Deactivation via N-dechloroethylation and activation via 4-hydroxylation catalyzed by distinct subsets of rat liver cytochromes P450

Drug Metabolism and Disposition : the Biological Fate of Chemicals
L Yu, D J Waxman

Abstract

The roles of individual liver cytochrome P450 (P450) enzymes in N-dechloroethylation leading to deactivation and neurotoxification of the isomeric alkylating agent prodrugs ifosfamide (IF) and cyclophosphamide (CPA) were investigated using an in vitro rat liver model. Rats were pretreated with a panel of drugs, including phenobarbital (a strong inducer of liver P450 2B1/2B2) and dexamethasone (a strong inducer of P450 3A enzymes), to examine the effects of these P450-inducing agents on IF and CPA N-dechloroethylation catalyzed by rat hepatic microsomes. The P450 3A-specific inhibitor troleandomycin and inhibitory monoclonal antibodies reactive with P450 2B and 2C enzymes were used to identify the individual P450 subfamilies involved in microsomal N-dechloroethylation of IF and CPA. It was found that dexamethasone pretreatment preferentially elevated microsomal CPA N-dechloroethylation activity (12-fold increase) and that P450 3A enzymes catalyzed up to > 95% of this reaction in both uninduced and drug-induced liver. In contrast, IF N-dechloroethylation activity was stimulated (approximately 8-fold increase) in liver microsomes by phenobarbital pretreatment, and P450 2B1/2B2 were responsible for the majority of this activity. In...Continue Reading

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