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Research ArticleArticle

Calcium Channel Modulators of the Dihydropyridine Family Are Human Pregnane X Receptor Activators and Inducers of CYP3A, CYP2B, and CYP2C in Human Hepatocytes

Lionel Drocourt, Jean-Marc Pascussi, Eric Assenat, Jean-Michel Fabre, Patrick Maurel and Marie-José Vilarem
Drug Metabolism and Disposition October 2001, 29 (10) 1325-1331;
Lionel Drocourt
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Jean-Marc Pascussi
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Eric Assenat
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Jean-Michel Fabre
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Patrick Maurel
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Marie-José Vilarem
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Abstract

The expression of three cytochromes P450 (CYP3A4, CYP2C9, and CYP2B6) was investigated in primary human hepatocyte cultures following treatment with four calcium channel modulators (CCM) of the dihydropyridine family, three antagonists (nifedipine, nicardipine, and isradipine), and one agonist (BK8644). Induction of CYP3A4 was studied by Northern blot, Western blot, and enzymatic activity. Induction began between 1 and 10 μM CCM and was dependent on the presence of dexamethasone (100 nM) in the medium. CYP3A4 mRNA accumulation started only after 16 h of treatment because pregnane X receptor (hPXR) synthesis was needed. Cotransfection experiments showed that the proximal and the distal PXR response elements of the CYP3A4 promoter and hPXR (HepG2 cells) or dexamethasone-induced hPXR (primary hepatocytes) were necessary to obtain full induction. Furthermore, glutathione S-transferase pull-down assays demonstrated that the CCM tested can act as hPXR ligands. In addition, cotransfection experiments in CV1 cells showed that these compounds failed to reverse CAR (constitutively activated receptor) inactivation by androstenol. Finally, 10 μM CCM induced both CYP2C9 and CYP2B6, strengthening the evidence that hPXR is involved in the regulation of these genes. All together, these results widen the field of hPXR activators to a new class of ligand, namely the CCM of the dihydropyridine family.

Footnotes

  • This work was supported in part by GlaxoWellcome (L.D.) and la Ligue Nationale contre le Cancer (J.-M.P.).

  • Abbreviations used are::
    CCM
    calcium channel modulators
    P450
    cytochrome P450
    PXR
    pregnane X receptor
    hPXR
    human PXR
    CAR
    constitutively activated receptor
    mCAR
    mouse CAR
    DMSO
    dimethyl sulfoxide
    TCPOBOP
    1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene
    PCR
    polymerase chain reaction
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    GST
    glutathione S-transferase
    PAGE
    polyacrylamide gel electrophoresis
    CSA
    cyclosporin A
    NIF
    nifedipine
    BK
    BK8644
    ISRA
    isradipine, RIF, rifampicin
    NIC
    nicardipine
    SRC
    steroid receptor coactivator
    PB
    phenobarbital
    DEX
    dexamethasone
    CARLA
    coactivator receptor ligand assay
    ER6
    everted repeat 6
    • Received March 26, 2001.
    • Accepted July 9, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (10)
Drug Metabolism and Disposition
Vol. 29, Issue 10
1 Oct 2001
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Research ArticleArticle

Calcium Channel Modulators of the Dihydropyridine Family Are Human Pregnane X Receptor Activators and Inducers of CYP3A, CYP2B, and CYP2C in Human Hepatocytes

Lionel Drocourt, Jean-Marc Pascussi, Eric Assenat, Jean-Michel Fabre, Patrick Maurel and Marie-José Vilarem
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1325-1331;

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Research ArticleArticle

Calcium Channel Modulators of the Dihydropyridine Family Are Human Pregnane X Receptor Activators and Inducers of CYP3A, CYP2B, and CYP2C in Human Hepatocytes

Lionel Drocourt, Jean-Marc Pascussi, Eric Assenat, Jean-Michel Fabre, Patrick Maurel and Marie-José Vilarem
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1325-1331;
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