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OtherDRUG METABOLISM AND DISPOSITION

Human Hepatocyte Growth Factor Down-regulates the Expression of Cytochrome P450 Isozymes in Human Hepatocytes in Primary Culture

M. Teresa Donato, M. José Gómez-Lechón, Ramiro Jover, Toshikazu Nakamura and José V. Castell
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 760-767;
M. Teresa Donato
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M. José Gómez-Lechón
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Ramiro Jover
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Toshikazu Nakamura
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José V. Castell
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Abstract

This study examines the effects of recombinant human hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, on the cytochrome P450 (CYP) system and conjugating reactions in cultured human hepatocytes. The time course of HGF effects on CYP1A1/2 (7-ethoxyresorufin O-deethylase) activity revealed that maximal inhibition was observed at 96 hr of culture. HGF produced a general decrease in the activity of all the CYP isozymes studied, namely CYP1A1/2 (7-ethoxyresorufin O-deethylase), CYP2B6 (7-benzoxyresorufin O-debenzylase), CYP2A6 (coumarin 7-hydroxylase), CYP2E1 (p-nitrophenol hydroxylase) and CYP3A4 (testosterone 6β-hydroxylase). In contrast, UDP-glucuronyltransferase and glutathione S-transferase activities and reduced glutathione levels were not modified significantly by the factor. When hepatocytes were treated with inducers, marked increases in the specific activities of CYP1A1/2 by 3-methylcholanthrene and CYP3A4 by rifampicin were observed, and these inductive effects were greatly reduced in the presence of HGF. Furthermore, CYP1A2 and CYP3A4 protein levels also dropped in the presence of HGF both in control and induced hepatocytes. The observed changes in the activity and protein levels of CYP1A2 and CYP3A4 correlated with a reduction in the specific messenger RNA levels both in control, 3-methylcholanthrene-treated (for CYP1A2) and rifampicin-treated (for CYP3A4) hepatocytes, which thus suggested that HGF could down-regulate CYP expression at a pretranslational level.

Footnotes

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

  • ↵1 This work was supported by the European Union (Project Nr. AIR-CT93–0860 and BMH4-CT96–0254).

  • Abbreviations:
    BROD
    7-benzoxyresorufin O-debenzylase
    CDNB
    1-chloro-2,4-dinitrobenzene
    CH
    coumarin 7-hydroxylase
    CYP
    cytochrome P450
    EGF
    epidermal growth factor
    EROD
    7-ethoxyresorufin O-deethylase
    GSH
    glutathione
    GST
    glutathioneS-transferase
    HGF
    hepatocyte growth factor
    MC
    3-methylcholanthrene
    nt
    nucleotides
    PNP
    p-nitrophenol hydroxylase
    RIF
    rifampicin
    mRNA
    messenger RNA
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    SDS
    sodium dodecyl sulfate
    TGFα
    transforming growth factor α
    UGT
    UDP-glucuronyltransferase
    6β-OHT
    testosterone 6β-hydroxylase
    • Received April 21, 1997.
    • Accepted October 20, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherDRUG METABOLISM AND DISPOSITION

Human Hepatocyte Growth Factor Down-regulates the Expression of Cytochrome P450 Isozymes in Human Hepatocytes in Primary Culture

M. Teresa Donato, M. José Gómez-Lechón, Ramiro Jover, Toshikazu Nakamura and José V. Castell
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 760-767;

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OtherDRUG METABOLISM AND DISPOSITION

Human Hepatocyte Growth Factor Down-regulates the Expression of Cytochrome P450 Isozymes in Human Hepatocytes in Primary Culture

M. Teresa Donato, M. José Gómez-Lechón, Ramiro Jover, Toshikazu Nakamura and José V. Castell
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 760-767;
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