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Molecular Pharmacology

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Research ArticleArticle

An Inducible Cytochrome P450 3A4-Dependent Vitamin D Catabolic Pathway

Zhican Wang, Yvonne S. Lin, Xi Emily Zheng, Tauri Senn, Takanori Hashizume, Michele Scian, Leslie J. Dickmann, Sidney D. Nelson, Thomas A. Baillie, Mary F. Hebert, David Blough, Connie L. Davis and Kenneth E. Thummel
Molecular Pharmacology April 2012, 81 (4) 498-509; DOI: https://doi.org/10.1124/mol.111.076356
Zhican Wang
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Yvonne S. Lin
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Xi Emily Zheng
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Tauri Senn
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Takanori Hashizume
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Michele Scian
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Leslie J. Dickmann
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Sidney D. Nelson
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Thomas A. Baillie
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Mary F. Hebert
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David Blough
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Connie L. Davis
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Kenneth E. Thummel
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Abstract

Vitamin D3 is critical for the regulation of calcium and phosphate homeostasis. In some individuals, mineral homeostasis can be disrupted by long-term therapy with certain antiepileptic drugs and the antimicrobial agent rifampin, resulting in drug-induced osteomalacia, which is attributed to vitamin D deficiency. We now report a novel CYP3A4-dependent pathway, the 4-hydroxylation of 25-hydroxyvitamin D3 (25OHD3), the induction of which may contribute to drug-induced vitamin D deficiency. The metabolism of 25OHD3 was fully characterized in vitro. CYP3A4 was the predominant source of 25OHD3 hydroxylation by human liver microsomes, with the formation of 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] dominating (Vmax/Km = 0.85 ml · min−1 · nmol enzyme−1). 4β,25(OH)2D3 was found in human plasma at concentrations comparable to that of 1α,25-dihydroxyvitamin D3, and its formation rate in a panel of human liver microsomes was strongly correlated with CYP3A4 content and midazolam hydroxylation activity. Formation of 4β,25(OH)2D3 in primary human hepatocytes was induced by rifampin and inhibited by CYP3A4-specific inhibitors. Short-term treatment of healthy volunteers (n = 6) with rifampin selectively induced CYP3A4-dependent 4β,25(OH)2D3, but not CYP24A1-dependent 24R,25-dihydroxyvitamin D3 formation, and altered systemic mineral homeostasis. Our results suggest that CYP3A4-dependent 25OHD3 metabolism may play an important role in the regulation of vitamin D3 in vivo and in the etiology of drug-induced osteomalacia.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM063666, P01-GM032165]; National Institutes of Health National Institute of Environmental Health Sciences [Grant P30-ES07033]; and National Institutes of Health National Institute of National Center for Research Resources [Grant GUL1-RR025014].

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

    http://dx.doi.org/10.1124/mol.111.076356.

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

  • ABBREVIATIONS:

    25OHD3
    25-hydroxyvitamin D3
    1α,25(OH)2D3
    1α,25-dihydroxyvitamin D3
    PXR
    pregnane X receptor
    DHB
    6′,7′-dihydroxybergamottin
    KTZ
    ketoconazole
    24R,25(OH)2D3
    24R,25-dihydroxyvitamin D3
    PTAD
    4-phenyl-1,2,4-triazoline-3,5-dione
    23R,25(OH)2D3
    23R,25-dihydroxyvitamin D3
    24S,25(OH)2D3
    24R,25-dihydroxyvitamin D3
    25,26(OH)2D3
    25,26-dihydroxyvitamin D3
    23S,25(OH)2D3
    23S,25-dihydroxyvitamin D3
    1α,25(OH)2-3-epi-D3
    1α,25-dihydroxy-3-epi-vitamin D3
    HLM
    human liver microsome(s)
    4,25(OH2)D3
    4,25-dihydroxyvitamin D3
    4α,25(OH)2D3
    4α,25-dihydroxyvitamin D3
    4β,25(OH)2D3
    4β,25-dihydroxyvitamin D3
    LLE
    liquid-liquid extraction
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    MRM
    multiple reaction monitoring
    GC
    gas chromatography
    MS
    electron impact mass spectrometry
    MDZ
    midazolam
    DMSO
    dimethyl sulfoxide.

  • Received October 13, 2011.
  • Accepted December 28, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (4)
Molecular Pharmacology
Vol. 81, Issue 4
1 Apr 2012
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Research ArticleArticle

Metabolism of 25-Hydroxyvitamin D3 by CYP3A4

Zhican Wang, Yvonne S. Lin, Xi Emily Zheng, Tauri Senn, Takanori Hashizume, Michele Scian, Leslie J. Dickmann, Sidney D. Nelson, Thomas A. Baillie, Mary F. Hebert, David Blough, Connie L. Davis and Kenneth E. Thummel
Molecular Pharmacology April 1, 2012, 81 (4) 498-509; DOI: https://doi.org/10.1124/mol.111.076356

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Research ArticleArticle

Metabolism of 25-Hydroxyvitamin D3 by CYP3A4

Zhican Wang, Yvonne S. Lin, Xi Emily Zheng, Tauri Senn, Takanori Hashizume, Michele Scian, Leslie J. Dickmann, Sidney D. Nelson, Thomas A. Baillie, Mary F. Hebert, David Blough, Connie L. Davis and Kenneth E. Thummel
Molecular Pharmacology April 1, 2012, 81 (4) 498-509; DOI: https://doi.org/10.1124/mol.111.076356
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