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OtherDRUG METABOLISM AND DISPOSITION

Oncostatin M Down-regulates Basal and Induced Cytochromes P450 in Human Hepatocytes

M. Isabel Guillén, M. Teresa Donato, Ramiro Jover, JoséV. Castell, R. Fabra, R. Trullenque and M. José Gómez-Lechón
Journal of Pharmacology and Experimental Therapeutics April 1998, 285 (1) 127-134;
M. Isabel Guillén
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M. Teresa Donato
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Ramiro Jover
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JoséV. Castell
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R. Fabra
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R. Trullenque
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M. José Gómez-Lechón
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Abstract

The effects of oncostatin M on the expression of different cytochrome P450 (CYP) isozymes has been investigated in human hepatocytes. The dose-response and time-course analyses of effects on CYP1A2 and CYP3A4 isozymes revealed that maximal inhibition was reached after 48 hr of exposure of human hepatocytes to 25 units/ml oncostatin M. Reductions in CYP1A2 and CYP3A4 activity produced by oncostatin M correlated with decreases in protein content, de novo protein synthesis and specific mRNA levels, thus suggesting that oncostatin M could down-regulate CYP expression at the transcriptional level. The inhibitory potency of oncostatin M on CYP expression was compared with that of other cytokines belonging to the interleukin-6 receptor family (interleukin-6, interleukin-11 and leukemia inhibitory factor), and interferon-γ, which is recognized to inhibit human CYP expression, and granulocyte colony-stimulating factor, a cytokine that shares structural homology with the interleukin-6 family but has a different transduction signal. Maximal reductions in CYP1A2 activity were reached after 48 hr of treatment with cytokines. At that time, oncostatin M showed the highest inhibitory effects on CYP1A2 activity (38% of control), followed by interferon (49% of control) and interleukin-6 (60% of control), whereas minor effects were produced by the other cytokines (74–80%). Comparable decreases were observed for CYP2A6, CYP2B6 and CYP3A4 activities. Enzymatic activity and de novoprotein synthesis of 3-methylcholanthrene-induced CYP1A2 and dexamethasone-induced CYP3A4 were also reduced to a much greater extent by oncostatin M than by other cytokines. The results show that oncostatin M is the most effective cytokine in down-regulating CYP isozymes in human hepatocytes, and its effects were evident even after removal of the cytokine from the culture medium.

Footnotes

  • Send reprint requests to: Dr. M. JoséGómez-Lechón, Unidad de Hepatologı́a Experimental, Centro de Investigación, Hospital Universitario La Fe, Avda. Campanar 21, Valencia-46009, Spain.

  • ↵1 The financial support of European Union (Project AIR2-CT93-0860, BMH1-CT94-1097 and BIO4-CT96-0052) and the ALIVE Foundation is gratefully acknowledged.

  • Abbreviations:
    CYP
    cytochrome P450
    DEX
    dexamethasone
    G-CSF
    granulocyte colony-stimulating factor
    IFN
    interferon-γ
    IL-1β
    interleukin-1β
    IL-6
    interleukin-6
    IL-11
    interleukin-11
    LIF
    leukemia inhibitory factor
    MC
    3-methylcholanthrene
    OSM
    oncostatin M
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    TGF-β
    transforming growth factor-β
    TNF-α
    tumor necrosis factor-α
    • Received June 30, 1997.
    • Accepted December 15, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 1
1 Apr 1998
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OtherDRUG METABOLISM AND DISPOSITION

Oncostatin M Down-regulates Basal and Induced Cytochromes P450 in Human Hepatocytes

M. Isabel Guillén, M. Teresa Donato, Ramiro Jover, JoséV. Castell, R. Fabra, R. Trullenque and M. José Gómez-Lechón
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 127-134;

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OtherDRUG METABOLISM AND DISPOSITION

Oncostatin M Down-regulates Basal and Induced Cytochromes P450 in Human Hepatocytes

M. Isabel Guillén, M. Teresa Donato, Ramiro Jover, JoséV. Castell, R. Fabra, R. Trullenque and M. José Gómez-Lechón
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 127-134;
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