Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements

Paul D. Thompson, Peter Jurutka, G. Kerr Whitfield, Sandy M. Myskowski, Kristina R. Eichhorst, Carlos Encinas Dominguez, Carol A. Haussler, Mark R. Haussler

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

The nuclear vitamin D receptor (VDR) mediates the effects of 1, 25-dihydroxyvitamin D3 1, 25D3 to alter intestinal gene transcription and promote calcium absorption. Because 1, 25D3 also exerts anti-cancer effects, we examined the efficacy of 1, 25D3 to induce cytochrome P450 (CYP) enzymes. Exposure of human colorectal adenocarcinoma cells (HT-29) to 108 M 1, 25D3 resulted in ≥3-fold induction of CYP3A4 mRNA and protein as assessed by RT-PCR and Western blotting, respectively. Six vitamin D responsive element (VDRE)-like sequences in the promoter region of the CYP3A4 gene were then individually tested for their ability to enhance transcription. A canonical DR3-type element in the distal region of the promoter(-7719-GGGTCAgcaAGTTCA-7733), and a proximal, non-classical everted repeat with a spacer of 6 bp (ER6; -169-TGAACTcaaaggAGGTCA-152) were identified as functional VDREs in this CYP gene. These data suggest that 1, 25D3-dependent, VDR-mediated induction of CYP3A4 may constitute a chemoprotective mechanism for detoxification of enteric xenobiotics and carcinogens.

Original languageEnglish (US)
Pages (from-to)730-738
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume299
Issue number5
DOIs
StatePublished - Jan 1 2002

Keywords

  • 1, 25-Dihydroxyvitamin D
  • Carcinogens
  • Chemoprevention
  • Cytochrome P450
  • Detoxification
  • Enterocytes
  • Nuclear vitamin D receptor
  • Pregnane X receptor
  • Retinoid X receptor
  • Xenobiotics

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Thompson, P. D., Jurutka, P., Whitfield, G. K., Myskowski, S. M., Eichhorst, K. R., Encinas Dominguez, C., Haussler, C. A., & Haussler, M. R. (2002). Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochemical and Biophysical Research Communications, 299(5), 730-738. https://doi.org/10.1016/S0006-291X(02)02742-0