1. Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements
- Author
-
Kristina R. Eichhorst, Carol A. Haussler, Sandy M Myskowski, Paul Thompson, G. Kerr Whitfield, Mark R. Haussler, Carlos Encinas Dominguez, and Peter W. Jurutka
- Subjects
Transcriptional Activation ,Biophysics ,Electrophoretic Mobility Shift Assay ,Retinoid X receptor ,Ligands ,Vitamin D Response Element ,Biochemistry ,Calcitriol receptor ,Calcitriol ,Cytochrome P-450 Enzyme System ,Transcription (biology) ,Intestinal Neoplasms ,Intestine, Small ,Tumor Cells, Cultured ,Cytochrome P-450 CYP3A ,Humans ,RNA, Messenger ,Molecular Biology ,Pregnane X receptor ,Messenger RNA ,biology ,Cytochrome P450 ,Promoter ,Cell Biology ,Molecular biology ,VDRE ,Gene Expression Regulation, Neoplastic ,Colonic Neoplasms ,biology.protein ,HT29 Cells - 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 10 −8 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- GGGTCA gca AGTTCA -7733), and a proximal, non-classical everted repeat with a spacer of 6 bp (ER6; -169- TGAACT caaagg AGGTCA -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.
- Published
- 2002
- Full Text
- View/download PDF