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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human CYP1B1 and Anticancer Agent Metabolism: Mechanism for Tumor-Specific Drug Inactivation?

Bertrand Rochat, Janine M. Morsman, Graeme I. Murray, William D. Figg and Howard L. McLeod
Journal of Pharmacology and Experimental Therapeutics February 2001, 296 (2) 537-541;
Bertrand Rochat
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Janine M. Morsman
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Graeme I. Murray
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William D. Figg
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Howard L. McLeod
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Abstract

The cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of procarcinogens and xenobiotics. Human CYP1B1 protein has been detected in a variety of tumors but is not detected in adjacent normal tissues or in liver. This suggests that CYP1B1 could biotransform anticancer agents specifically in the target cells. The interaction between CYP1B1 and 12 commonly used anticancer drugs was screened using an ethoxyresorufin deethylase assay. Four agents were competitive inhibitors of CYP1B1 activity: flutamide (K i = 1.0 μM), paclitaxel (K i = 31.6 μM), mitoxantrone (K i = 11.6 μM), and docetaxel (K i = 28.0 μM). Doxorubicin (K i = 2.6 μM) and daunomycin (K i = 2.1 μM) were mixed inhibitors, while tamoxifen was a noncompetitive inhibitor (K i = 5.0 μM). Vinblastine, vincristine, 5-fluorouracil, etoposide, and cyclophosphamide did not inhibit CYP1B1 activity. In vitro incubations with flutamide and CYP1B1 produced a metabolite consistent with 2-hydroxyflutamide. Comparison of kinetic parameters (K m,K i, V max) for flutamide 2-hydroxylation by CYP1B1, CYP1A1, and CYP1A2 indicate that CYP1B1 could play a major role for flutamide biotransformation in tumors. The results obtained indicate that several anticancer agents inhibit CYP1B1 activity. Drug inactivation by CYP1B1 may represent a novel mechanism of resistance, influencing the clinical outcome of chemotherapy.

Footnotes

    • Received April 10, 2000.
    • Accepted September 28, 2000.
  • Send reprint requests to: Dr. Howard L. McLeod, Washington University School of Medicine, Department of Medicine, Room 1021 CSRB NT, 660 South Euclid Ave., Campus Box 8069, St. Louis, MO 63110-1093. E-mail: hmcleod{at}imgate.wustl.edu

  • This work was supported in part by grants from the Aberdeen Royal Infirmary Endowment Office and The Chief Scientist Office of Scotland.

  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 2
1 Feb 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human CYP1B1 and Anticancer Agent Metabolism: Mechanism for Tumor-Specific Drug Inactivation?

Bertrand Rochat, Janine M. Morsman, Graeme I. Murray, William D. Figg and Howard L. McLeod
Journal of Pharmacology and Experimental Therapeutics February 1, 2001, 296 (2) 537-541;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human CYP1B1 and Anticancer Agent Metabolism: Mechanism for Tumor-Specific Drug Inactivation?

Bertrand Rochat, Janine M. Morsman, Graeme I. Murray, William D. Figg and Howard L. McLeod
Journal of Pharmacology and Experimental Therapeutics February 1, 2001, 296 (2) 537-541;
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