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Vol. 296, Issue 2, 537-541, February 2001
Departments of Medicine and Therapeutics (B.R., J.M.M., H.L.M.) and
Pathology (G.I.M.), University of Aberdeen, Aberdeen, Scotland; and
Medicine Branch, Division of Clinical Sciences, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland (W.D.F.)
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
(Ki = 1.0 µM), paclitaxel (Ki = 31.6 µM), mitoxantrone
(Ki = 11.6 µM), and docetaxel
(Ki = 28.0 µM). Doxorubicin
(Ki = 2.6 µM) and daunomycin
(Ki = 2.1 µM) were mixed inhibitors,
while tamoxifen was a noncompetitive inhibitor
(Ki = 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 (Km,
Ki, Vmax) 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.
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