Affordable Access

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

Authors
  • Thompson, Paul D
  • Jurutka, Peter W
  • Whitfield, G Kerr
  • Myskowski, Sandy M
  • Eichhorst, Kristina R
  • Dominguez, Carlos Encinas
  • Haussler, Carol A
  • Haussler, Mark R
Type
Published Article
Journal
Biochemical and biophysical research communications
Publication Date
Dec 20, 2002
Volume
299
Issue
5
Pages
730–738
Identifiers
PMID: 12470639
Source
Medline
License
Unknown

Abstract

The nuclear vitamin D receptor (VDR) mediates the effects of 1,25-dihydroxyvitamin D(3) (1,25D(3)) to alter intestinal gene transcription and promote calcium absorption. Because 1,25D(3) also exerts anti-cancer effects, we examined the efficacy of 1,25D(3) to induce cytochrome P450 (CYP) enzymes. Exposure of human colorectal adenocarcinoma cells (HT-29) to 10(-8)M 1,25D(3) 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 1,25D(3)-dependent, VDR-mediated induction of CYP3A4 may constitute a chemoprotective mechanism for detoxification of enteric xenobiotics and carcinogens.

Report this publication

Statistics

Seen <100 times