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Drug Metabolism and Disposition Fast Forward
First published on May 26, 2005; DOI: 10.1124/dmd.105.004788

0090-9556/05/3309-1261-1267$20.00
DMD 33:1261-1267, 2005

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ENANTIOSELECTIVE METABOLISM AND CYTOTOXICITY OF R-IFOSFAMIDE AND S-IFOSFAMIDE BY TUMOR CELL-EXPRESSED CYTOCHROMES P450

Chong-Sheng Chen, Youssef Jounaidi, and David J. Waxman

Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts

The anticancer prodrug ifosfamide (IFA) contains a chiral phosphorous atom and is administered in the clinic as a racemic mixture of R-IFA and S-IFA. Hepatic cytochrome P450 (P450) enzymes exhibit enantioselective preferences in the metabolism of R-IFA and S-IFA; however, the impact of this selectivity on P450-dependent anticancer activity is not known. Presently, the metabolism and cytotoxicity of R-IFA and S-IFA were determined in 9L gliosarcoma and Chinese hamster ovary tumor cells expressing an IFA-activating P450 enzyme and by in vitro steady-state kinetic analysis using cDNA-expressed P450 enzymes. Tumor cells expressing P450 enzyme CYP3A4 were the most sensitive to R-IFA cytotoxicity, whereas tumor cells expressing CYP2B1 or CYP2B6 were most sensitive to cyclophosphamide (CPA), an isomer of IFA. Correspondingly, CYP3A4-expressing cells and cDNA-expressed CYP3A4 metabolized R-IFA to yield the active, 4-hydroxylated metabolite at a 2- to 3-fold higher rate than they metabolized S-IFA or CPA. CYP2B cells and cDNA-expressed CYP2B enzymes metabolized CPA almost exclusively by 4-hydroxylation, whereas R-IFA and S-IFA were substantially converted to inactive, N-dechloroethylated metabolites. Further investigation revealed that CYP3A1, a rat enzyme, exhibited superior kinetic properties compared with the human enzyme CYP3A4, with R-IFA and S-IFA both metabolized with high catalytic efficiency by 4-hydroxylation and with a Km value of 200 µM, ~5-fold lower than CYP3A4. Based on these kinetic parameters and metabolic profiles, R-IFA is expected to exert greater anticancer activity than S-IFA or CPA against tumors that express CYP3A enzymes, whereas tumors expressing CYP2B enzymes may be more sensitive to CPA treatment.

Address correspondence to: Dr. David J. Waxman, Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215. E-mail: djw{at}bu.edu




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J. Gu, C.-S. Chen, Y. Wei, C. Fang, F. Xie, K. Kannan, W. Yang, D. J. Waxman, and X. Ding
A Mouse Model with Liver-Specific Deletion and Global Suppression of the NADPH-Cytochrome P450 Reductase Gene: Characterization and Utility for in Vivo Studies of Cyclophosphamide Disposition
J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 9 - 17.
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