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

doi:10.1016/S0006-291X(02)02742-0

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 journal › Article › peer-review

134 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 language	English (US)
Pages (from-to)	730-738
Number of pages	9
Journal	Biochemical and Biophysical Research Communications
Volume	299
Issue number	5
DOIs	https://doi.org/10.1016/S0006-291X(02)02742-0
State	Published - 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

Thompson, PD, Jurutka, P, Whitfield, GK, Myskowski, SM, Eichhorst, KR, Encinas Dominguez, C, Haussler, CA & Haussler, MR 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, vol. 299, no. 5, pp. 730-738. https://doi.org/10.1016/S0006-291X(02)02742-0

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

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.",

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author = "Thompson, {Paul D.} and Peter Jurutka and Whitfield, {G. Kerr} and Myskowski, {Sandy M.} and Eichhorst, {Kristina R.} and {Encinas Dominguez}, Carlos and Haussler, {Carol A.} and Haussler, {Mark R.}",

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AU - Thompson, Paul D.

AU - Jurutka, Peter

AU - Whitfield, G. Kerr

AU - Myskowski, Sandy M.

AU - Eichhorst, Kristina R.

AU - Encinas Dominguez, Carlos

AU - Haussler, Carol A.

AU - Haussler, Mark R.

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AB - 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.

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KW - Carcinogens

KW - Chemoprevention

KW - Cytochrome P450

KW - Detoxification

KW - Enterocytes

KW - Nuclear vitamin D receptor

KW - Pregnane X receptor

KW - Retinoid X receptor

KW - Xenobiotics

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

Abstract

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