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Science 17 May 2002:
Vol. 296. no. 5571, pp. 1313 - 1316
DOI: 10.1126/science.1070477
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Reports

Vitamin D Receptor As an Intestinal Bile Acid Sensor

Makoto Makishima,1* Timothy T. Lu,1 Wen Xie,2dagger G. Kerr Whitfield,3 Hideharu Domoto,1 Ronald M. Evans,2 Mark R. Haussler,3 David J. Mangelsdorf1ddagger

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.

1 Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9050, USA.
2 Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, Post Office Box 85800, San Diego, CA 92186-5800, USA.
3 Department of Biochemistry and Molecular Biophysics, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
*   Present address: Department of Organismal Biosystems, Osaka University, Suita, Osaka 565-0871, Japan.

dagger    Present address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.

ddagger    To whom correspondence should be addressed. E-mail: davo.mango{at}utsouthwestern.edu

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Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor.
B. Goodwin, K. C. Gauthier, M. Umetani, M. A. Watson, M. I. Lochansky, J. L. Collins, E. Leitersdorf, D. J. Mangelsdorf, S. A. Kliewer, and J. J. Repa (2003)
PNAS 100, 223-228
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Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR).
J. Sonoda, W. Xie, J. M. Rosenfeld, J. L. Barwick, P. S. Guzelian, and R. M. Evans (2002)
PNAS 99, 13801-13806
   Abstract »    Full Text »    PDF »
Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors.
J. Y. L. Chiang (2002)
Endocr. Rev. 23, 443-463
   Abstract »    Full Text »    PDF »


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Science. ISSN 0036-8075 (print), 1095-9203 (online)