Regulation of CYP3A4 and CYP3A5 expression and modulation of "intracrine" metabolism of androgens in prostate cells by liganded vitamin D receptor

Orla Maguire, Catherine Pollock, Philip Martin, Andrew Owen, Thomas Smyth, Declan Doherty, Moray J Campbell, Stephen McClean, Paul Thompson

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

We investigated the capacity for vitamin D receptor (VDR) to modulate the expression of CYP3A4 and other genes that may facilitate the oxidative inactivation of androgens such as testosterone and androstanediol within prostate cells. We report that exposure to the active hormonal form of vitamin D markedly increased gene expression of CYP3A4 and CYP3A5 and ultimately achieved levels of intracellular CYP3A enzyme activity within LNCaP prostate cancer cells that were comparable to that observed for Caco2 cells, an established model of CYP3A induction, and resulted in the increased turnover of testosterone to its inactive 6β-OH metabolite. We demonstrate that VDR directs CYP3A4 and CYP3A5 expression through binding to distinct regulatory motifs located within the 5' promoter regions of both genes. The current data highlight the potential application of VDR-based treatment regimes as a means to limit the bioavailability of growth-promoting androgens within the tumor microenvironment.

Original languageEnglish
Pages (from-to)54-64
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume364
Issue number1-2
DOIs
Publication statusPublished - 25 Nov 2012

Bibliographical note

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Keywords

  • Androstenediol/metabolism
  • Caco-2 Cells
  • Calcitriol/metabolism
  • Cell Line, Tumor
  • Cytochrome P-450 CYP3A/genetics
  • Cytochrome P-450 CYP4A/genetics
  • Gene Expression Regulation/drug effects
  • Humans
  • Ligands
  • Male
  • Promoter Regions, Genetic
  • Prostate/drug effects
  • Prostatic Neoplasms/enzymology
  • Receptors, Calcitriol/genetics
  • Testosterone/metabolism
  • Transfection

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