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Identification of the major human hepatic cytochrome P450 involved in activation and N-dechloroethylation of ifosfamide

Lookup NU author(s): Professor Alan Boddy, Emerita Professor Suzanne Cholerton, Professor Ann Daly, Professor Andrew Pearson

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Abstract

Two NADPH-dependent metabolic routes for the anticancer drug ifosfamide, 4-hydroxylation (activation) and N-dechloroethylation (a detoxication pathway),were studied in human liver microsomes to identify the cytochrome P450 enzymes involved. Naringenin, a grapefruit aglycone and an inhibitor of cytochrome P450 3A4 (CYP3A4)-catalysed reactions, was found to inhibit ifosfamide activation and N-dechloroethylation by human liver microsomes. IC50 for both reactions was of the order of 70 mu M. The CYP3A4-specific inhibitor triacetyloleandomycin inhibited ifosfamide N-dechloroethylation by human Liver microsomes with an IC50 Of approximately 10 mu M. Furthermore, anti-human CYP3A4 antiserum inhibited by about 80% N-dechloroethylation of ifosfamide by human liver microsomes. The relative levels of cytochromes P450 1A, 2C, 2E and 3A4 in 12 human livers were determined by western blotting analysis. A strong correlation (P < 0.001) was observed between CYP3A4 expression and both activation and N-dechloroethylation of ifosfamide. A role for human CYP3A4 in both pathways of ifosfamide metabolism was thus demonstrated. This was substantiated by the observation that the nifedipine oxidase activities of the 12 samples of human liver microsomes correlated with ifosfamide activation (P < 0.009) and N-dechloroethylation (P < 0.001). These findings have important clinical implications. The involvement of the same key cytochrome P450 enzyme in both reactions prohibits selective inhibition of the N-dechloroethylation pathway, as might be desirable to reduce toxic side effects. They also demonstrate the need to consider interaction with co-administered drugs that are CYP3A4 substrates.


Publication metadata

Author(s): Walker, D., Flinois, J. P., Monkman, S. C., Beloc, C., Boddy, A. V., Cholerton, S., Daly, A. K., Lind, M. J., Pearson, A. D. J., Beaune, P. H., Idle, J. R.

Publication type: Article

Publication status: Published

Journal: Biochemical Pharmocology

Year: 1994

Volume: 47

Issue: 7

Pages: 1157-1163

Print publication date: 29/03/1994

ISSN (print): 0006-2952

ISSN (electronic): 1873-2968

URL: http://dx.doi.org/10.1016/0006-2952(94)90387-5

DOI: 10.1016/0006-2952(94)90387-5


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