Abstract
The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are other nuclear receptors. Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestine. These studies offer a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Aryl Hydrocarbon Hydroxylases*
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Binding, Competitive
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COS Cells
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Cell Line
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Colonic Neoplasms / prevention & control
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism
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DNA-Binding Proteins / metabolism
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Dimerization
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Gene Expression Regulation, Enzymologic
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Histone Acetyltransferases
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Humans
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Intestine, Small / metabolism*
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Ligands
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Lithocholic Acid / analogs & derivatives
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Lithocholic Acid / metabolism*
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Lithocholic Acid / pharmacology
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Male
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Mice
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Nuclear Receptor Coactivator 1
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism
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Pregnane X Receptor
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Promoter Regions, Genetic
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Rats
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Receptors, Calcitriol / agonists
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Receptors, Calcitriol / genetics
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Receptors, Calcitriol / metabolism*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Steroid / metabolism
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Transcription Factors / metabolism
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Transfection
Substances
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3-ketolithocholic acid
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DNA-Binding Proteins
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Ligands
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Pregnane X Receptor
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Receptors, Calcitriol
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Transcription Factors
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farnesoid X-activated receptor
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Lithocholic Acid
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Cytochrome P-450 Enzyme System
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP3A
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Oxidoreductases, N-Demethylating
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Histone Acetyltransferases
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NCOA1 protein, human
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Ncoa1 protein, mouse
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Nuclear Receptor Coactivator 1