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J. Biol. Chem., Vol. 281, Issue 26, 17882-17889, June 30, 2006

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Role of NF-B in Regulation of PXR-mediated Gene Expression

A MECHANISM FOR THE SUPPRESSION OF CYTOCHROME P-450 3A4 BY PROINFLAMMATORY AGENTS^*

Xinsheng Gu, Sui Ke, Duan Liu, Tao Sheng, Paul E. Thomas^¶, Arnold B. Rabson^¶, Michael A. Gallo^¶, Wen Xie^||, and Yanan Tian¹

From the Texas A & M University, College Station, Texas 77843, the ^||Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania 15213, the ^¶EOSHI and Rutgers University, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and the University of Texas Medical Branch, Galveston, Texas 77555

It is a long-standing observation that inflammatory responses and infections decrease drug metabolism capacity in human and experimental animals. Cytochrome P-450 3A4 cyp304 is responsible for the metabolism of over 50% of current prescription drugs, and cyp3a4 expression is transcriptionally regulated by pregnane X receptor (PXR), which is a ligand-dependent transcription factor. In this study, we report that NF-B activation by lipopolysaccharide and tumor necrosis factor- plays a pivotal role in the suppression of cyp3a4 through interactions of NF-B with the PXR·retinoid X receptor (RXR) complex. Inhibition of NF-B by NF-B-specific suppressor SRIB reversed the suppressive effects of lipopolysaccharide and tumor necrosis factor-. Furthermore, we showed that NF-B p65 disrupted the association of the PXR·RXR complex with DNA sequences as determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. NF-B p65 directly interacted with the DNA-binding domain of RXR and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by the PXR·RXR complex. This mechanism of suppression by NF-B activation may be extended to other nuclear receptor-regulated systems where RXR is a dimerization partner.

Received for publication, February 9, 2006 , and in revised form, April 3, 2006.

^* This work was supported in part by NIEHS, National Institutes of Health Grants ES 09859 and ES 09106 and American Heart Association Grant 0355131Y. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Veterinary Physiology and Pharmacology, Mail Stop 4466, Texas A & M University, College Station, TX 77843. Tel.: 979-458-3599; Fax: 979-458-4485; E-mail: ytian{at}cvm.tamu.edu.

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