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Research ArticleArticle

Effects of Interleukin-6 (IL-6) and an Anti-IL-6 Monoclonal Antibody on Drug-Metabolizing Enzymes in Human Hepatocyte Culture

Leslie J. Dickmann, Sonal K. Patel, Dan A. Rock, Larry C. Wienkers and J. Greg Slatter
Drug Metabolism and Disposition August 2011, 39 (8) 1415-1422; DOI: https://doi.org/10.1124/dmd.111.038679
Leslie J. Dickmann
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Sonal K. Patel
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Dan A. Rock
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Larry C. Wienkers
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J. Greg Slatter
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Abstract

The cytokine-mediated suppression of hepatic drug-metabolizing enzymes by inflammatory disease and the relief of this suppression by successful disease treatment have recently become an issue in the development of drug interaction labels for new biological products. This study examined the effects of the inflammatory cytokine interleukin-6 (IL-6) on drug-metabolizing enzymes in human hepatocyte culture and the abrogation of these effects by a monoclonal antibody directed against IL-6. Treatment of human hepatocytes with IL-6 (n = 9 donors) revealed pan-suppression of mRNA of 10 major cytochrome P450 isoenzymes, but with EC50 values that differed by isoenzyme. Some EC50 values were above the range of clinically relevant serum concentrations of IL-6. Marker activities for CYP1A2 and CYP3A4 enzyme were similarly suppressed by IL-6 in both freshly isolated and cryopreserved hepatocytes. IL-6 suppressed induction of CYP1A2 enzyme activity by omeprazole and CYP3A4 enzyme activity by rifampicin but only at supraphysiological concentrations of IL-6. Glycosylated and nonglycosylated IL-6 did not significantly differ in their ability to suppress CYP1A2 and CYP3A4 enzyme activity. A monoclonal antibody directed against IL-6 abolished or partially blocked IL-6-mediated suppression of CYP1A2 and CYP3A4 enzyme activity, respectively. These data indicate that experimentation with IL-6 and anti-IL-6 monoclonal antibodies in human hepatocyte primary culture can quantitatively measure cytochrome P450 suppression and desuppression and determine EC50 values for IL-6 against individual cytochrome P450 isoenzymes. However, the complex biology of inflammatory disease may not allow for quantitative in vitro-in vivo extrapolation of these simple in vitro data.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.038679.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    IL-6
    interleukin-6
    IL-6R
    IL-6 receptor
    P450
    cytochrome P450
    APR
    acute-phase response
    NF-κB
    nuclear factor κ-light-chain enhancer of activated B cells
    CAR
    constitutive androstane receptor
    PXR
    pregnane X receptor
    HEK
    human embryonic kidney
    KHB
    Krebs-Henseleit buffer
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    DP
    declustering potential
    CE
    collision energy
    CXP
    collision cell exit potential
    CRP
    C-reactive protein
    SAA
    serum amyloid A
    C/EBP
    CCAAT/enhancer-binding protein
    STAT3
    signal transducer and activator of transcription 3.

  • Received February 10, 2011.
  • Accepted May 9, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (8)
Drug Metabolism and Disposition
Vol. 39, Issue 8
1 Aug 2011
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Research ArticleArticle

Effects of Interleukin-6 (IL-6) and an Anti-IL-6 Monoclonal Antibody on Drug-Metabolizing Enzymes in Human Hepatocyte Culture

Leslie J. Dickmann, Sonal K. Patel, Dan A. Rock, Larry C. Wienkers and J. Greg Slatter
Drug Metabolism and Disposition August 1, 2011, 39 (8) 1415-1422; DOI: https://doi.org/10.1124/dmd.111.038679

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Research ArticleArticle

Effects of Interleukin-6 (IL-6) and an Anti-IL-6 Monoclonal Antibody on Drug-Metabolizing Enzymes in Human Hepatocyte Culture

Leslie J. Dickmann, Sonal K. Patel, Dan A. Rock, Larry C. Wienkers and J. Greg Slatter
Drug Metabolism and Disposition August 1, 2011, 39 (8) 1415-1422; DOI: https://doi.org/10.1124/dmd.111.038679
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