Bioactivation of tamoxifen by recombinant human cytochrome P450 enzymes

Notely, Lisa M., de Wolf, Cornelia J. F., Wunsch, Rebecca M., Lancaster, Roy G. and Gillam, Elizabeth M. J. (2002) Bioactivation of tamoxifen by recombinant human cytochrome P450 enzymes. Chemical Research in Toxicology, 15 5: 614-622.


Author Notely, Lisa M.
de Wolf, Cornelia J. F.
Wunsch, Rebecca M.
Lancaster, Roy G.
Gillam, Elizabeth M. J.
Title Bioactivation of tamoxifen by recombinant human cytochrome P450 enzymes
Journal name Chemical Research in Toxicology   Check publisher's open access policy
Publication date 2002
Sub-type Article
DOI 10.1021/tx0100439
Volume number 15
Issue number 5
ISSN 0893-228X
Start page 614
End page 622
Total pages 9
Editor L. J. Marnett
Place of publication Washington
Publisher American Chemical Society
Collection year 2002
Language eng
Subject C1
270108 Enzymes
780105 Biological sciences
Abstract Tamoxifen is a major drug used for adjuvant chemotherapy of breast cancer; however, its use has been associated with a small but significant increase in risk of endometrial cancer. In rats, tamoxifen is a hepatocarcinogen, and DNA adducts have been observed in both rat and human tissues. Tamoxifen has been shown previously to be metabolized to reactive products that have the potential to form protein and DNA adducts. Previous studies have suggested a role for P450 3A4 in protein adduct formation in human liver microsomes, via a catechol intermediate; however, no clear correlation was seen between P450 3A4 content of human liver microsomes and adduct formation. In the present study, we investigated the P450 forms responsible for covalent drug-protein adduct formation and the possibility that covalent adduct formation might occur via alternative pathways to catechol formation. Recombinant P450 3A4 catalyzed adduct formation, and this correlated with the level of uncoupling in the P450 incubation, consistent with a role of reactive oxygen species in potentiating adduct formation after enzymatic formation of the catechol metabolite. Whereas P450s 1AI, 2D6, and 3A5 generated catechol metabolite, no covalent adduct formation was observed with these forms. By contrast, P450 2136, 2C19, and rat liver microsomes catalyzed drug-protein adduct formation but not catechol formation. Drug protein adducts formed specifically with P450 3A4 in incubations using membranes isolated from bacteria expressing P450 3A4 and reductase, as well as in reconstitutions of purified 3A4, suggesting that the electrophilic species reacted preferentially with the P450 enzymes concerned.
Keyword Chemistry, Medicinal
Chemistry, Multidisciplinary
Toxicology
Human Liver-microsomes
Antiestrogenic Agent Tamoxifen
Surgical-adjuvant-breast
Escherichia-coli
Dna-adducts
Alpha-hydroxytamoxifen
Covalent Binding
Catalytic Characterization
Rat Hepatocytes
Cancer Patients
Q-Index Code C1
Additional Notes We reported that the covalent binding of the breast cancer drug tamoxifen to protein, a surrogate measure of tamoxifen bioactivation to genotoxic metabolites, was due to formation of semi/quinone species and potentiated by oxidising conditions found in some recombinant systems. The principal target of adduct formation was found to be the catalytic P450. IF 2.797, 14 citations to date.

Document type: Journal Article
Sub-type: Article
Collections: Excellence in Research Australia (ERA) - Collection
School of Biomedical Sciences Publications
 
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