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Research ArticleArticle

The Effect of Cyclophosphamide with and without Dexamethasone on Cytochrome P450 3A4 and 2B6 in Human Hepatocytes

Celeste Lindley, Geraldine Hamilton, Jeannine S. McCune, Stephanie Faucette, Stacy S. Shord, Roy L. Hawke, Hongbing Wang, Darryl Gilbert, Summer Jolley, Bingfang Yan and Edward L. LeCluyse
Drug Metabolism and Disposition July 2002, 30 (7) 814-822; DOI: https://doi.org/10.1124/dmd.30.7.814
Celeste Lindley
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Geraldine Hamilton
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Jeannine S. McCune
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Stephanie Faucette
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Stacy S. Shord
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Roy L. Hawke
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Hongbing Wang
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Darryl Gilbert
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Summer Jolley
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Bingfang Yan
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Edward L. LeCluyse
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Abstract

The purpose of this study was to characterize the concentration-response effects of cyclophosphamide (CPA) with and without dexamethasone (DEX; 10 μM) on the expression of CYP3A4 and CYP2B6 in cultured human hepatocytes at concentrations representative of standard- and high-dose CPA therapy (25 to 750 μM). CPA produced concentration-dependent increases in CYP3A4 and CYP2B6 activity and immunoreactive protein that peaked at 250 and 125 μM, respectively, and declined thereafter. The inductive effect of CPA alone and in combination with DEX was greater in magnitude for CYP2B6 compared with CYP3A4. To further examine the inductive effect of CPA on CYP3A4, CPA (250 μM) and DEX (10 μM) alone and in combination were examined in 10 hepatocyte preparations. The combination of CPA and DEX yielded higher rates of 6β-hydroxytestosterone formation than either agent alone. However, the effect was less than additive in human hepatocyte cultures with relatively high baseline CYP3A4 activity and additive or synergistic in human hepatocyte cultures with relatively low baseline CYP3A4 activity. Induction index was highly correlated with CYP3A4 baseline activity for both CPA (r2 = 0.75) and CPA plus DEX (r2 = 0.85). To investigate the potential mechanism for CPA-induced increases in CYP3A4 activity, the ability of CPA alone and in combination with DEX to activate pregnane X receptor (PXR) was explored using transient transfection assays. CPA produced a dose-dependent increase in PXR activation that was maximal at the highest CPA concentration studied (500 μM). The addition of DEX to CPA resulted in a minor increase in PXR activation compared with CPA alone. These results indicate that CPA alone and in combination with DEX differentially induces the expression of CYP3A4 and 2B in a concentration-dependent manner, which may be mediated partially through activation of PXR. The impact of these effects on the efficacy and toxicity of CPA therapy warrants further investigation.

Footnotes

  • This work was supported in part by a Hollingsworth Faculty Scholarship awarded to Celeste Lindley by the School of Pharmacy, University of North Carolina at Chapel Hill, and by a Food and Drug Administration Center for Drug Evaluation and Research contract 223-97-3004.

  • Abbreviations used are::
    CPA
    cyclophosphamide
    P450
    cytochrome P450
    PXR
    pregnane X receptor
    DEX
    dexamethasone
    HBUP
    hydroxybupropion
    HPLC
    high-performance liquid chromatography
    DMEM
    Dulbecco's modified Eagle's medium
    • Received June 4, 2001.
    • Accepted March 28, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (7)
Drug Metabolism and Disposition
Vol. 30, Issue 7
1 Jul 2002
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Research ArticleArticle

The Effect of Cyclophosphamide with and without Dexamethasone on Cytochrome P450 3A4 and 2B6 in Human Hepatocytes

Celeste Lindley, Geraldine Hamilton, Jeannine S. McCune, Stephanie Faucette, Stacy S. Shord, Roy L. Hawke, Hongbing Wang, Darryl Gilbert, Summer Jolley, Bingfang Yan and Edward L. LeCluyse
Drug Metabolism and Disposition July 1, 2002, 30 (7) 814-822; DOI: https://doi.org/10.1124/dmd.30.7.814

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Research ArticleArticle

The Effect of Cyclophosphamide with and without Dexamethasone on Cytochrome P450 3A4 and 2B6 in Human Hepatocytes

Celeste Lindley, Geraldine Hamilton, Jeannine S. McCune, Stephanie Faucette, Stacy S. Shord, Roy L. Hawke, Hongbing Wang, Darryl Gilbert, Summer Jolley, Bingfang Yan and Edward L. LeCluyse
Drug Metabolism and Disposition July 1, 2002, 30 (7) 814-822; DOI: https://doi.org/10.1124/dmd.30.7.814
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