Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation?

Details

Serval ID
serval:BIB_1B33C70F9E83
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation?
Journal
Journal of Pharmacology and Experimental Therapeutics
Author(s)
Rochat  B., Morsman  J. M., Murray  G. I., Figg  W. D., McLeod  H. L.
ISSN
0022-3565 (Print)
Publication state
Published
Issued date
02/2001
Volume
296
Number
2
Pages
537-41
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Feb
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 microM), paclitaxel (K(i) = 31.6 microM), mitoxantrone (K(i) = 11.6 microM), and docetaxel (K(i) = 28.0 microM). Doxorubicin (K(i) = 2.6 microM) and daunomycin (K(i) = 2.1 microM) were mixed inhibitors, while tamoxifen was a noncompetitive inhibitor (K(i) = 5.0 microM). 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.
Keywords
Antineoplastic Agents/*metabolism Antineoplastic Agents, Hormonal/metabolism/pharmacology *Aryl Hydrocarbon Hydroxylases Biotransformation Cytochrome P-450 CYP1A1/antagonists & inhibitors/metabolism Cytochrome P-450 Enzyme System/antagonists & inhibitors/*metabolism Flutamide/metabolism/pharmacology Humans Hydroxylation Kinetics Mixed Function Oxygenases/*antagonists & inhibitors/metabolism Neoplasms/*enzymology Tumor Cells, Cultured
Pubmed
Web of science
Create date
25/01/2008 8:47
Last modification date
20/08/2019 12:51
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