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Research ArticleArticle

The Aromatase Inactivator 4-Hydroxyandrostenedione (4-OH-A) Inhibits Tamoxifen Metabolism by Rat Hepatic Cytochrome P-450 3A: Potential for Drug-Drug Interaction of Tamoxifen and 4-OH-A in Combined Anti-Breast Cancer Therapy

Shangara S. Dehal, Angela M. H. Brodie and David Kupfer
Drug Metabolism and Disposition March 1999, 27 (3) 389-394;
Shangara S. Dehal
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Angela M. H. Brodie
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David Kupfer
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Abstract

Tamoxifen (tam), an anti-breast cancer agent, is metabolized into tam-N-oxide by the hepatic flavin-containing monooxygenase and into N-desmethyl- and 4-hydroxy-tam by cytochrome P-450s (CYPs). Additionally, tam is metabolically activated by hepatic CYP3A, forming a reactive intermediate that binds covalently to proteins. Tam and 4-hydroxyandrostenedione (4-OH-A) are currently used to treat breast cancer, and it has been contemplated that 4-OH-A be given concurrently with tam to contravene potential tumor resistance to tam. Because alterations in tam metabolism may influence its therapeutic efficacy, the effect of 4-OH-A on tam metabolism was examined. Incubation of tam with liver microsomes from phenobarbital-treated rats, in the presence of 4-OH-A (10–100 μM), resulted in marked inhibition of tam-N-demethylation and tam covalent binding and in decreased tam-N-oxide accumulation; however, there was no inhibition of the formation of 4-hydroxy-tam and of 3,4-dihydroxytamoxifen. These findings indicate that 4-OH-A inhibits CYP3A, but not P-450(s) that catalyze tam 4-hydroxylation. The diminished tam-N-oxide accumulation could be due to decreased N-oxide formation and/or due to increasedN-oxide reduction. Incubation of tam-N-oxide with liver microsomes containing heat-inactivated flavin-containing monooxygenase demonstrated that 4-OH-A increases the accumulation of tam, possibly by diminishing its P-450-mediated metabolism. Kinetic studies indicate that 4-OH-A is a competitive inhibitor of CYP3A, but not a time-dependent inactivator. Consequently, the concurrent treatment of tam and 4-OH-A may result in increased tam half-life and thus could potentiate the therapeutic efficacy of tam and diminish the potential side effects of tam by inhibiting its covalent binding to proteins and possibly to DNA.

Footnotes

  • Send reprint requests to: Dr. David Kupfer, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, 55 Lake Ave. N., Worcester, Massachusetts. E-mail:david.kupfer{at}ummed.edu

  • This work was supported by National Institute of Health Grants ES00834 (DK) and CA62483 (AB) from the National Institute of Environmental Health Sciences and the National Cancer Institute, respectively, and by a starter grant from the Board of Trustees of the Worcester Foundation (DK). The contents reported are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Environmental Health Sciences, the National Cancer Institute and the National Institutes of Health. A preliminary account of a portion of this investigation was presented at the Experimental Biology meeting in Washington, DC,FASEB J10:1020 (1996)

  • Abbreviations used are::
    tam
    tamoxifen [Z (1-(4-(2-dimethylaminoethoxy) phenyl]-1,2-diphenyl-1-butene]
    FMO
    flavin-containing monooxygenase
    CYP
    cytochrome P-450
    PB
    phenobarbital
    4-OH-A
    4-hydroxyandrostenedione
    4-OH-tam
    4-hydroxytamoxifen
    [3H]SAM
    [3H-methyl]S-adenosyl-l-methionine
    TLC
    thin-layer chromatography
    DTT
    dithiothreitol
    PB-microsomes
    liver microsomes from PB-treated rats
    • Received October 9, 1998.
    • Accepted December 2, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (3)
Drug Metabolism and Disposition
Vol. 27, Issue 3
1 Mar 1999
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The Aromatase Inactivator 4-Hydroxyandrostenedione (4-OH-A) Inhibits Tamoxifen Metabolism by Rat Hepatic Cytochrome P-450 3A: Potential for Drug-Drug Interaction of Tamoxifen and 4-OH-A in Combined Anti-Breast Cancer Therapy
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Research ArticleArticle

The Aromatase Inactivator 4-Hydroxyandrostenedione (4-OH-A) Inhibits Tamoxifen Metabolism by Rat Hepatic Cytochrome P-450 3A: Potential for Drug-Drug Interaction of Tamoxifen and 4-OH-A in Combined Anti-Breast Cancer Therapy

Shangara S. Dehal, Angela M. H. Brodie and David Kupfer
Drug Metabolism and Disposition March 1, 1999, 27 (3) 389-394;

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Research ArticleArticle

The Aromatase Inactivator 4-Hydroxyandrostenedione (4-OH-A) Inhibits Tamoxifen Metabolism by Rat Hepatic Cytochrome P-450 3A: Potential for Drug-Drug Interaction of Tamoxifen and 4-OH-A in Combined Anti-Breast Cancer Therapy

Shangara S. Dehal, Angela M. H. Brodie and David Kupfer
Drug Metabolism and Disposition March 1, 1999, 27 (3) 389-394;
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