Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements.
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.
Thompson
Paul D
PD
Department of Biochemistry and Molecular Biophysics, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
Jurutka
Peter W
PW
Whitfield
G Kerr
GK
Myskowski
Sandy M
SM
Eichhorst
Kristina R
KR
Dominguez
Carlos Encinas
CE
Haussler
Carol A
CA
Haussler
Mark R
MR
D002117:Calcitriol / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008024:Ligands; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D030181:Vitamin D Response Element
D008024:Ligands; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002117:Calcitriol