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Research ArticleArticle

Induction of UGT1A1 and CYP2B6 by an Antimitogenic Factor in HepG2 Cells Is Mediated through Suppression of Cyclin-Dependent Kinase 2 Activity: Cell Cycle-Dependent Expression

Junko Sugatani, Makoto Osabe, Masatoshi Kurosawa, Naomi Kitamura, Akira Ikari and Masao Miwa
Drug Metabolism and Disposition January 2010, 38 (1) 177-186; DOI: https://doi.org/10.1124/dmd.109.029785
Junko Sugatani
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Makoto Osabe
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Masatoshi Kurosawa
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Naomi Kitamura
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Akira Ikari
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Masao Miwa
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Abstract

Hepatocyte growth factor (HGF), an antimitogenic factor for HepG2 cells, increased mRNA and protein levels of UGT1A1 and CYP2B6, as well as the endogenous cyclin-dependent kinase (CDK) inhibitors p16, p21, and p27 in HepG2 cells but not in HuH6, Caco2, or MCF7 cells. Treatment with 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) (an extracellular signal-regulated kinase inhibitor) suppressed the HGF-induced expression of UGT1A1 and CYP2B6, as well as p16, p21, and p27 in HepG2 cells. The CDK inhibitor roscovitine also enhanced the expression of UGT1A1, CYP2B6, and CYP3A4. Transfection of anti-CDK2 siRNA led to elevated levels of UGT1A1, CYP2B6, and CYP3A4 in HepG2 and SW480 cells, whereas anti-CDK4 small interfering RNA (siRNA) did not significantly enhance the expression of these enzymes. In fact, CDK2 activity was decreased in HGF-treated HepG2 cells. In cells arrested in S phase by a thymidine block and then released into a synchronous cell cycle, there was a clear dissociation among the activation of CDK2 and the expression of UGT1A1, CYP2B6, and CYP3A4. Furthermore, the induction of CYP3A4 but not UGT1A1 or CYP2B6 mRNA expression by roscovitine was repressed in pregnane X receptor (PXR) siRNA-transfected HepG2 cells. Transfection with constitutive androstane receptor siRNA or PXR siRNA in HepG2 cells did not repress the HGF-stimulated expression of UGT1A1 mRNA. Taken together, our results show that the expression of UGT1A1 and CYP2B6 is negatively regulated through a CDK2 signaling pathway linked to cell cycle progression in HepG2 and SW480 cells, the mechanism of which may differ from that of CYP3A4 expression through PXR phosphorylated by CDK2.

Footnotes

  • This work was supported in part by the 21st Century Center of Excellence (COE21) Program, Global COE, a grant-in-aid for Scientific Research [Grants 19590070, 19590151, and 21590170]; and Cooperation of Innovative Technology from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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

    doi:10.1124/dmd.109.029785

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

  • CAR
    constitutive androstane receptor
    PXR
    pregnane X receptor
    PB
    phenobarbital
    GR
    glucocorticoid receptor
    AhR
    aryl hydrocarbon receptor
    P450
    cytochrome P450
    EGF
    epidermal growth factor
    TCPOBOP
    1,4-bis[2-(3,5-dichloropyridyloxy)]benzene
    ERK
    extracellular signal-regulated kinase
    HGF
    hepatocyte growth factor
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(phenylthio)butadiene
    CDK
    cyclin-dependent kinase
    U0124
    1,4-diamino-2,3-dicyano-1,4-bis(aminomethylthio)butadiene
    LY294002
    2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
    SP600125
    anthra[1,9-cd]pyrazole-6 (2H)-one
    SU9516
    3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one
    PDGF
    platelet-derived growth factor
    DMEM
    Dulbecco's modified Eagle's medium
    FCS
    fetal calf serum
    siRNA
    small interfering RNA
    PCR
    polymerase chain reaction
    RXR
    retinoid X receptor
    CPR
    NADPH-cytochrome P450 reductase
    PI3
    phosphatidylinositol 3
    JNK
    c-Jun NH2-terminal kinase
    bp
    base pair
    WY-14643
    4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid
    BSA
    bovine serum albumin.

    • Received August 3, 2009.
    • Accepted September 28, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (1)
Drug Metabolism and Disposition
Vol. 38, Issue 1
1 Jan 2010
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Research ArticleArticle

Induction of UGT1A1 and CYP2B6 by an Antimitogenic Factor in HepG2 Cells Is Mediated through Suppression of Cyclin-Dependent Kinase 2 Activity: Cell Cycle-Dependent Expression

Junko Sugatani, Makoto Osabe, Masatoshi Kurosawa, Naomi Kitamura, Akira Ikari and Masao Miwa
Drug Metabolism and Disposition January 1, 2010, 38 (1) 177-186; DOI: https://doi.org/10.1124/dmd.109.029785

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Research ArticleArticle

Induction of UGT1A1 and CYP2B6 by an Antimitogenic Factor in HepG2 Cells Is Mediated through Suppression of Cyclin-Dependent Kinase 2 Activity: Cell Cycle-Dependent Expression

Junko Sugatani, Makoto Osabe, Masatoshi Kurosawa, Naomi Kitamura, Akira Ikari and Masao Miwa
Drug Metabolism and Disposition January 1, 2010, 38 (1) 177-186; DOI: https://doi.org/10.1124/dmd.109.029785
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