These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: 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.
    Author: Yu L, Waxman DJ.
    Journal: Drug Metab Dispos; 1996 Nov; 24(11):1254-62. PubMed ID: 8937861.
    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 addition, P450 2C11 catalyzed approximately 50% of IF N-dechloroethylation in uninduced male rat liver microsomes. inducers of P450 1A and 4A enzymes had no effect on N-dechloroethylation of IF or CPA. These P450 enzyme patterns for the N-dechloroethylation reaction are distinct from those previously determined for IF and CPA activation via 4-hydroxylation. In accord with this observation, the balance between oxazaphosphorine activation (4-hydroxylation pathway) and deactivation/neurotoxication (N-dechloroethylation pathway) could be modulated by P450 form-selective inducers and inhibitors. Thus, dexamethasone pretreatment substantially decreased the extent of IF N-dechloroethylation, from 47% to 24% of total metabolism, whereas it increased CPA N-dechloroethylation from 29% to 84% of total metabolism. Moreover, troleandomycin selectively inhibited CPA N-dechloroethylation, thereby increasing net metabolism of the drug via the therapeutically productive 4-hydroxylation pathway. Oxazaphosphorine activation and deactivation/neurotoxication are thus catalyzed by distinct subsets of liver P450 enzymes, in a manner that may allow for improvements in therapeutic indices for this class of drugs by using P450 form-selective modulators.
    [Abstract] [Full Text] [Related] [New Search]