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Research ArticleArticle

Induction of CYP3A4 by 1α,25-Dihydroxyvitamin D3 Is Human Cell Line-Specific and Is Unlikely to Involve Pregnane X Receptor

Phyllissa Schmiedlin-Ren, Kenneth E. Thummel, Jeannine M. Fisher, Mary F. Paine and Paul B. Watkins
Drug Metabolism and Disposition November 2001, 29 (11) 1446-1453;
Phyllissa Schmiedlin-Ren
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Kenneth E. Thummel
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Jeannine M. Fisher
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Mary F. Paine
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Paul B. Watkins
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Abstract

Under certain culture conditions, exposure of the human colon adenocarcinoma cell line Caco-2 to 1,25-(OH)2-D3 induces expression of CYP3A4 to levels comparable to that in human small intestinal epithelium. To determine whether 1,25-(OH)2-D3 could be used to restore CYP3A expression in other culture models, we examined several cell lines derived from malignancies of human tissues known to express CYP3A enzymes: Hep G2 (liver), LS180 (colon), HPAC (pancreas), Hs746T (stomach). Primary cultures of human hepatocytes from two donors were also examined. 1,25-(OH)2-D3 increased CYP3A catalytic activity in LS180 (15-fold), HPAC (6-fold), and hepatocytes (2- to 3-fold); this was accompanied by induction of CYP3A4 mRNA and CYP3A immunoreactive protein. However, 1,25-(OH)2-D3had no effect on CYP3A expression in Hs746T or Hep G2. Known ligands for pregnane X receptor (PXR) (rifampin, dexamethasone, and dexamethasone t-butyl acetate) markedly induced CYP3A4 expression in human hepatocytes. In contrast, these ligands had little or no effect on CYP3A4 expression in Caco-2 cells, even at concentrations 1 to 2 orders of magnitude greater than effective concentrations of 1,25-(OH)2-D3 or two other vitamin D receptor (VDR) ligands (25-OH-D3 and 1-OH-D3). The retinoic acid receptor ligand all-trans-retinoic acid augmented the 1,25-(OH)2-D3-mediated induction of CYP3A4 catalytic activity up to 2-fold in Caco-2 cells, while having no demonstrable effect on levels of CYP3A4 mRNA or protein. The retinoid X receptor ligand 9-cis-retinoic acid appeared to slightly reduce CYP3A4 catalytic activity. We conclude that 1,25-(OH)2-D3 can be used to increase CYP3A4 expression in some, but not all, human cell lines derived from tissues known to express CYP3A enzymes. The mechanisms involved in this induction are unlikely to involve PXR and may involve VDR.

Footnotes

  • ↵1 J.M.F. is presently affiliated with Pfizer, Groton, CT.

  • This research was supported by National Institutes of Health Grants GM 38149 (to P.B.W.) and GM 48349 (to K.E.T.).

  • Abbreviations used::
    CYP
    cytochrome P450
    1,25-(OH)2-D3
    1α,25-dihydroxyvitamin D3
    VDR
    vitamin D receptor (intracellular)
    1-OH-D3
    1α-hydroxyvitamin D3
    25-OH-D3
    25-hydroxyvitamin D3
    PXR
    pregnane X receptor
    PET
    polyethylene terephthalate
    MDZ
    midazolam
    1′-OH-MDZ
    1′-hydroxymidazolam
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    HPLC
    high-pressure liquid chromatography
    PCN
    pregnenolone 16α-carbonitrile
    DtBA
    dexamethasonet-butyl acetate
    D2-1′-OH-MDZ
    deuterated 1′-hydroxymidazolam
    GC/MS
    gas chromatography/mass spectrometry
    RT-PCR
    reverse transcription-polymerase chain reaction
    PAGE
    polyacrylamide gel electrophoresis
    LC/MS
    liquid chromatography/mass spectrometry
    RXR
    retinoid X receptor
    9-cis-RA
    9-cis-retinoic acid
    RAR
    retinoic acid receptor
    ATRA
    all-trans-retinoic acid
    TES
    N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid
    • Received April 16, 2001.
    • Accepted August 6, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (11)
Drug Metabolism and Disposition
Vol. 29, Issue 11
1 Nov 2001
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Research ArticleArticle

Induction of CYP3A4 by 1α,25-Dihydroxyvitamin D3 Is Human Cell Line-Specific and Is Unlikely to Involve Pregnane X Receptor

Phyllissa Schmiedlin-Ren, Kenneth E. Thummel, Jeannine M. Fisher, Mary F. Paine and Paul B. Watkins
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1446-1453;

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Research ArticleArticle

Induction of CYP3A4 by 1α,25-Dihydroxyvitamin D3 Is Human Cell Line-Specific and Is Unlikely to Involve Pregnane X Receptor

Phyllissa Schmiedlin-Ren, Kenneth E. Thummel, Jeannine M. Fisher, Mary F. Paine and Paul B. Watkins
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1446-1453;
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