QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.104.000299v1 32/10/1075    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, C. Articles by Blumberg, B. Search for Related Content PubMed PubMed Citation Articles by Zhou, C. Articles by Blumberg, B.

TOCOTRIENOLS ACTIVATE THE STEROID AND XENOBIOTIC RECEPTOR, SXR, AND SELECTIVELY REGULATE EXPRESSION OF ITS TARGET GENES

Department of Developmental and Cell Biology, University of California, Irvine, California

Vitamin E is an essential nutrient with antioxidant activity. Vitamin E is comprised of eight members, -, ß-, -, and -tocopherols and -, ß-, -, and -tocotrienols. All forms of vitamin E are initially metabolized by -oxidation, which is catalyzed by cytochrome P450 enzymes. The steroid and xenobiotic receptor (SXR) is a nuclear receptor that regulates drug clearance in the liver and intestine via induction of genes involved in drug and xenobiotic metabolism. We show here that all four tocotrienols specifically bind to and activate SXR, whereas tocopherols neither bind nor activate. Surprisingly, tocotrienols show tissue-specific induction of SXR target genes, particularly CYP3A4. Tocotrienols up-regulate expression of CYP3A4 but not UDP-glucuronosyltransferase 1A1 (UGT1A1) or multidrug resistance protein-1 (MDR1) in primary hepatocytes. In contrast, tocotrienols induce MDR1 and UGT1A1 but not CYP3A4 expression in intestinal LS180 cells. We found that nuclear receptor corepressor (NCoR) is expressed at relatively high levels in intestinal LS180 cells compared with primary hepatocytes. The unliganded SXR interacts with NCoR, and this interaction is only partially disrupted by tocotrienols. Expression of a dominant-negative NCoR enhanced the ability of tocotrienols to induce CYP3A4 in LS180 cells, suggesting that NCoR plays an important role in tissue-specific gene regulation by SXR. Our findings provide a molecular mechanism explaining how vitamin supplements affect the absorption and effectiveness of drugs. Knowledge of drug-nutrient interactions may help reduce the incidence of decreased drug efficacy.

This article has been cited by other articles:

				V. Chu, H. J. Einolf, R. Evers, G. Kumar, D. Moore, S. Ripp, J. Silva, V. Sinha, M. Sinz, and A. Skerjanec In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective Drug Metab. Dispos., July 1, 2009; 37(7): 1339 - 1354. [Abstract] [Full Text] [PDF]

				S. Harmsen, A. S. Koster, J. H. Beijnen, J. H. M. Schellens, and I. Meijerman Comparison of Two Immortalized Human Cell Lines to Study Nuclear Receptor-Mediated CYP3A4 Induction Drug Metab. Dispos., June 1, 2008; 36(6): 1166 - 1171. [Abstract] [Full Text] [PDF]

				N. Akaho, J. Takata, T. Fukushima, K. Matsunaga, A. Hattori, R. Hidaka, K. Fukui, M. Yoshida, T. Fujioka, Y. Karube, et al. Preparation and In Vivo Evaluation of a Water-Soluble Prodrug for 2R-{gamma}-Tocotrienol and as a Two-Step Prodrug for 2,7,8-Trimethyl-2S-({beta}-carboxyethyl)-6-hydroxychroman (S-{gamma}-CEHC) in Rat Drug Metab. Dispos., September 1, 2007; 35(9): 1502 - 1510. [Abstract] [Full Text] [PDF]

				S. Ekins, C. Chang, S. Mani, M. D. Krasowski, E. J. Reschly, M. Iyer, V. Kholodovych, N. Ai, W. J. Welsh, M. Sinz, et al. Human Pregnane X Receptor Antagonists and Agonists Define Molecular Requirements for Different Binding Sites Mol. Pharmacol., September 1, 2007; 72(3): 592 - 603. [Abstract] [Full Text] [PDF]

				M. G Traber Heart disease and single-vitamin supplementation Am. J. Clinical Nutrition, January 1, 2007; 85(1): 293S - 299S. [Abstract] [Full Text] [PDF]

				C. Zhou, E.-J. Poulton, F. Grun, T. K. Bammler, B. Blumberg, K. E. Thummel, and D. L. Eaton The Dietary Isothiocyanate Sulforaphane Is an Antagonist of the Human Steroid and Xenobiotic Nuclear Receptor Mol. Pharmacol., January 1, 2007; 71(1): 220 - 229. [Abstract] [Full Text] [PDF]

				B.-L. Song and R. A. DeBose-Boyd Insig-dependent Ubiquitination and Degradation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Stimulated by {delta}- and {gamma}-Tocotrienols J. Biol. Chem., September 1, 2006; 281(35): 25054 - 25061. [Abstract] [Full Text] [PDF]

				I. Meijerman, J. H. Beijnen, and J. H.M. Schellens Herb-Drug Interactions in Oncology: Focus on Mechanisms of Induction Oncologist, July 1, 2006; 11(7): 742 - 752. [Abstract] [Full Text] [PDF]

				Y. Miki, T. Suzuki, K. Kitada, N. Yabuki, R. Shibuya, T. Moriya, T. Ishida, N. Ohuchi, B. Blumberg, and H. Sasano Expression of the Steroid and Xenobiotic Receptor and Its Possible Target Gene, Organic Anion Transporting Polypeptide-A, in Human Breast Carcinoma Cancer Res., January 1, 2006; 66(1): 535 - 542. [Abstract] [Full Text] [PDF]

				S. Mani, H. Huang, S. Sundarababu, W. Liu, G. Kalpana, A. B. Smith, and S. B. Horwitz Activation of the Steroid and Xenobiotic Receptor (Human Pregnane X Receptor) by Nontaxane Microtubule-Stabilizing Agents Clin. Cancer Res., September 1, 2005; 11(17): 6359 - 6369. [Abstract] [Full Text] [PDF]

				S. W. Leonard, E. Gumpricht, M. W. Devereaux, R. J. Sokol, and M. G. Traber Quantitation of rat liver vitamin E metabolites by LC-MS during high-dose vitamin E administration J. Lipid Res., May 1, 2005; 46(5): 1068 - 1075. [Abstract] [Full Text] [PDF]