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Rapid CommunicationAccelerated Communication

Induction of Cytochrome P450 3A4 in Primary Human Hepatocytes and Activation of the Human Pregnane X Receptor by Tamoxifen and 4-Hydroxytamoxifen

Pankaj B. Desai, Srikanth C. Nallani, Rucha S. Sane, Linda B. Moore, Bryan J. Goodwin, Donna J. Buckley and Arthur R. Buckley
Drug Metabolism and Disposition May 2002, 30 (5) 608-612; DOI: https://doi.org/10.1124/dmd.30.5.608
Pankaj B. Desai
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Srikanth C. Nallani
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Rucha S. Sane
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Linda B. Moore
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Bryan J. Goodwin
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Donna J. Buckley
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Arthur R. Buckley
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Abstract

Tamoxifen is a widely utilized antiestrogen in the treatment and chemoprevention of breast cancer. Clinical studies document that tamoxifen administration markedly enhances the systemic elimination of other drugs. Additionally, tamoxifen enhances its own clearance following repeated dosing. The mechanisms that underlie these clinically important events remain unresolved. Here, we report that tamoxifen and its metabolite 4-hydroxytamoxifen markedly induce cytochrome P450 3A4, a drug-metabolizing enzyme of central importance, in primary cultures of human hepatocytes. Tamoxifen and 4-hydroxytamoxifen (1–10 μM) significantly increased the CYP3A4 expression and activity (measured as the rate of testosterone 6β-hydroxylation). Maximal induction was achieved at the 5 μM level. At this level, tamoxifen and 4-hydroxytamoxifen caused a 1.5- to 3.3-fold (mean, 2.1-fold) and 3.4- to 17-fold (mean, 7.5-fold) increase in the CYP3A4 activity, respectively. In comparison, rifampicin treatment resulted in a 6- to 16-fold (mean, 10.5-fold) increase. We also observed corresponding increase in the CYP3A4 immunoreactive protein and mRNA levels. Furthermore, tamoxifen and 4-hydroxytamoxifen efficaciously activated the human pregnane X receptor (hPXR; also known as the steroid xenobiotic receptor), a key regulator ofCYP3A4 expression. The efficacy of tamoxifen and 4-hydroxytamoxifen relative to rifampicin for hPXR activation was ∼30 and 60%, respectively. Our results indicate that the mechanism of tamoxifen-mediated alteration in drug clearance pathways in humans may involve CYP3A4 induction by the parent drug and/or its metabolite. Furthermore, the CYP3A4 induction may be a result of hPXR activation. These findings have important implications for optimizing the use of tamoxifen and in the development of newer antiestrogens.

Footnotes

  • Supported by a grant from the American Cancer Society (Ohio Division), Women's Health Program, University of Cincinnati Medical Center, the National Institutes of Health (DK53452), and the American Institute for Cancer Research.

  • Abbreviations used are::
    P450
    cytochrome P450
    hPXR
    human pregnane X receptor
    XREM
    xenobiotic response element module
    DMSO
    dimethyl sulfoxide
    HuH7
    human hepatocellular carcinoma
    HPLC
    high-performance liquid chromatography
    • Received January 2, 2002.
    • Accepted February 7, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (5)
Drug Metabolism and Disposition
Vol. 30, Issue 5
1 May 2002
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Rapid CommunicationAccelerated Communication

Induction of Cytochrome P450 3A4 in Primary Human Hepatocytes and Activation of the Human Pregnane X Receptor by Tamoxifen and 4-Hydroxytamoxifen

Pankaj B. Desai, Srikanth C. Nallani, Rucha S. Sane, Linda B. Moore, Bryan J. Goodwin, Donna J. Buckley and Arthur R. Buckley
Drug Metabolism and Disposition May 1, 2002, 30 (5) 608-612; DOI: https://doi.org/10.1124/dmd.30.5.608

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Rapid CommunicationAccelerated Communication

Induction of Cytochrome P450 3A4 in Primary Human Hepatocytes and Activation of the Human Pregnane X Receptor by Tamoxifen and 4-Hydroxytamoxifen

Pankaj B. Desai, Srikanth C. Nallani, Rucha S. Sane, Linda B. Moore, Bryan J. Goodwin, Donna J. Buckley and Arthur R. Buckley
Drug Metabolism and Disposition May 1, 2002, 30 (5) 608-612; DOI: https://doi.org/10.1124/dmd.30.5.608
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