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Research ArticleArticle

Involvement of Cyclic Nucleotide- and Calcium-Regulated Pathways in Phenobarbital-Induced Cytochrome P-450 3A Expression in Mouse Primary Hepatocytes

Milagros Galisteo, Nathalie Marc, Alain Fautrel, André Guillouzo, Laurent Corcos and Dominique Lagadic-Gossmann
Journal of Pharmacology and Experimental Therapeutics September 1999, 290 (3) 1270-1277;
Milagros Galisteo
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Nathalie Marc
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Alain Fautrel
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André Guillouzo
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Laurent Corcos
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Dominique Lagadic-Gossmann
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Abstract

Several of the hepatic microsomal cytochromes P-450 (CYP) including CYP3A are inducible by phenobarbital (PB). However, the intracellular pathways involved in the action of PB on CYP3A remain poorly known. With the aim to unravel some of the main aspects of PB signaling, we first devised a simple model of mouse cultured primary hepatocytes in which CYP3A mRNA and protein were strongly induced by PB in the absence of dexamethasone and were at maximum levels after a 48-h treatment with a 2-mM dose of PB. Under these culture conditions, we studied the effects of inhibitors and activators of different protein kinases or phosphatases on CYP3A mRNA and protein induction by PB. CYP3A-induced expression was inhibited by activators of cyclic AMP-dependent protein kinase (PKA) (dibutyryl-cyclic AMP and forskolin) whereas inhibition of PKA by PKA inhibitor enhanced induction. 8-br-cGMP produced effects similar to the activators of PKA, and so did the specific inhibitor of cGMP-dependent protein kinase, β-phenyl-1,N2-etheno-8-bromoguanosine-3,5′-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-PET-cGMPS). Inhibition of Ca2+/calmodulin-dependent protein kinase by KN-62 or the intracellular Ca2+ chelator BAPTA-AM produced an inhibition of CYP3A induction by PB. Specific inhibitors of protein kinase C, mitogen-activated protein kinase kinase, phosphatidylinositol-3-kinase, or serine/threonine phosphatase did not produce any effect. Taken together, our results suggest that CYP3A induction by PB is regulated positively by calmodulin-dependent protein kinase and cGMP-dependent protein kinase, and negatively by PKA in mouse hepatocytes in primary culture.

Footnotes

  • Send reprint requests to: Dr. D. Lagadic-Gossmann, INSERM U456, Détoxication et Réparation Tissulaire, Facultédes Sciences Pharmaceutiques et Biologiques, Université de Rennes I, 2, Avenue du Professeur Léon Bernard, 35043 Rennes cedex, France. E-mail: Dominique.Lagadic{at}rennes.inserm.fr

  • ↵1 This work was supported by the Institut National de la Sante et de la Recherche Medicale and European Economic Community contract EUROCYP: BMH4-CT96–0254. M.G. is a recipient of a postdoctoral fellowship from the “Universidad de Granada” (Spain). N.M. is a recipient of a fellowship from the “Ministère de la Recherche et de l’Enseignement Supérieur” (France).

  • ↵2 Present address: Institut National de la Sante et de la Recherche Medicale U517, Faculté de Médecine, 7 Boulevard Jeanne d’Arc, 21033 Dijon Cedex, France.

  • Abbreviations:
    CYP
    cytochrome P-450
    PB
    phenobarbital
    cAMP
    cyclic AMP
    PKA
    cAMP-dependent protein kinase
    PKG
    cGMP-dependent protein kinase
    CaM PK
    Ca2+/calmodulin-dependent protein kinase
    PKC
    protein kinase C
    MAP
    mitogen-activated protein
    Rp-8-Br-PET-cGMPS
    β-phenyl-1,N2-etheno-8-bromoguanosine-3′,5′-cyclic monophosphorothioate, Rp-isomer
    db-cAMP
    N6,O2-dibutyryl-cAMP
    PKAI
    protein kinase A inhibitor
    ITS
    5 mg/l insulin, 2.25 mg/l transferrin, 2.5 mg/l sodium selenite
    SSC
    standard sodium citrate
    TBS
    Tris-buffered saline
    CREB
    cAMP response element-binding protein
    • Received March 31, 1999.
    • Accepted May 18, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 3
1 Sep 1999
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Research ArticleArticle

Involvement of Cyclic Nucleotide- and Calcium-Regulated Pathways in Phenobarbital-Induced Cytochrome P-450 3A Expression in Mouse Primary Hepatocytes

Milagros Galisteo, Nathalie Marc, Alain Fautrel, André Guillouzo, Laurent Corcos and Dominique Lagadic-Gossmann
Journal of Pharmacology and Experimental Therapeutics September 1, 1999, 290 (3) 1270-1277;

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Research ArticleArticle

Involvement of Cyclic Nucleotide- and Calcium-Regulated Pathways in Phenobarbital-Induced Cytochrome P-450 3A Expression in Mouse Primary Hepatocytes

Milagros Galisteo, Nathalie Marc, Alain Fautrel, André Guillouzo, Laurent Corcos and Dominique Lagadic-Gossmann
Journal of Pharmacology and Experimental Therapeutics September 1, 1999, 290 (3) 1270-1277;
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