Abstract
The central nervous system toxicity of ifosfamide (IFF), a chiral antineoplastic agent, is thought to be dependent on itsN-dechloroethylation by hepatic cytochrome P-450 (CYP) enzymes. The purpose of this study was to identify the human CYPs responsible for IFF-N-dechloroethylation and their corresponding regio- and enantioselectivities. IFF exists in two enantiomeric forms, (R) - and (S)-IFF, which can be dechloroethylated at either the N2 or N3 positions, producing the corresponding (R,S)-2-dechloroethyl-IFF [(R,S)-2-DCE-IFF] and (R,S)-3-dechloroethyl-IFF [(R,S)-3-DCE-IFF]. The results of the present study suggest that the production of (R)-2-DCE-IFF and (S)-3-DCE-IFF from (R)-IFF is catalyzed by different CYPs as is the production of (S)-2-DCE-IFF and (R)-3-DCE-IFF from (S)-IFF. In vitro studies with a bank of human liver microsomes revealed that the sample-to-sample variation in the production of (S)-3-DCE-IFF from (R)-IFF and (S)-2-DCE-IFF from (S)-IFF was highly correlated with the levels of (S)-mephenytoinN-demethylation (CYP2B6), whereas (R)-2-DCE-IFF production from (R)-IFF and (R)-3-DCE-IFF production from (S)-IFF were both correlated with the activity of testosterone 6β-hydroxylation (CYP3A4/5). Experiments with cDNA-expressed P-450 and antibody and chemical inhibition studies supported the conclusion that the formation of (S)-3-DCE-IFF and (S)-2-DCE-IFF is catalyzed primarily by CYP2B6, whereas (R)-2-DCE-IFF and (R)-3-DCE-IFF are primarily the result of CYP3A4/5 activity.
Footnotes
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Send reprint requests to: Irving W. Wainer, Ph.D., Georgetown University, Department of Pharmacology, Room C-305, Medical-Dental Building, Washington, DC 20007-2197. E-mail:waineri{at}gunet.georgetown.edu
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This work was supported in part by grants from the Cancer Research Society, Inc. and ChiroScience Ltd. and by the National Institute of Environmental Health and Sciences (Grant ES03765).
- Abbreviations used are::
- IFF
- ifosfamide
- (R)-IFF and (S)-IFF
- (R)- and (S)-ifosfamide
- (R,S)-2-DCE-IFF and (R,S)-3-DCE-IFF
- (R,S)-2-dechloroethyl-IFF and (R,S)-3-dechloroethyl-IFF
- CYP or P-450
- cytochrome P-450
- Received July 31, 1998.
- Accepted January 4, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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