Abstract
Vitamin E is an essential nutrient with antioxidant activity. Vitamin E is comprised of eight members, α-, β-, γ-, and δ-tocopherols and α-, β-, γ-, and δ-tocotrienols. All forms of vitamin E are initially metabolized by ω-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.
Footnotes
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This work was supported by grants from the National Institutes of Health (GM-60572), the U.S. Environmental Protection Agency (STAR G1T1 0704), and the Department of Defense (DAMD17-02-1-0323) to B.B. Normal human hepatocytes were obtained through the Liver Tissue Procurement and Distribution System (Pittsburgh, PA) funded by National Institutes of Health Contract N01-DK-9-2310. A.S. was the recipient of a University of California, Irvine Undergraduate Research Opportunity Grant.
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doi:10.1124/dmd.104.000299.
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ABBREVIATIONS: P450, cytochrome P450; SXR, steroid and xenobiotic receptor; UGT1A1, UDP-glucuronosyltransferase 1A1; MDR1, multidrug resistance protein-1; QRT-PCR, quantitative real-time polymerase chain reaction; NCoR, nuclear receptor corepressor; DN-NCoR, dominant-negative NCoR; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; EtOH, ethanol; RIF, rifampicin; RU486, mifepristone; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; SRC-1, steroid receptor coactivator-1; GRIP-1, glucocorticoid receptor interacting protein-1; ACTR, activator of thyroid and retinoic acid receptor; PBP, peroxisome proliferator-activated receptor-binding protein; SMRT, silencing mediator of retinoid and thyroid hormone; SERM, selective estrogen receptor modulator; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; SR12813, 3,5-di-tert-butyl-4-hydroxystyrene-β,β -diphosphonic acid tetraethyl ester.
- Received April 15, 2004.
- Accepted July 9, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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