title: Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents.
abstract: 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-kappaB activation by lipopolysaccharide and tumor necrosis factor-alpha plays a pivotal role in the suppression of cyp3a4 through interactions of NF-kappaB with the PXR.retinoid X receptor (RXR) complex. Inhibition of NF-kappaB by NF-kappaB-specific suppressor SRIkappaBalpha reversed the suppressive effects of lipopolysaccharide and tumor necrosis factor-alpha. Furthermore, we showed that NF-kappaB p65 disrupted the association of the PXR.RXRalpha complex with DNA sequences as determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. NF-kappaB p65 directly interacted with the DNA-binding domain of RXRalpha and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by the PXR.RXRalpha complex. This mechanism of suppression by NF-kappaB activation may be extended to other nuclear receptor-regulated systems where RXRalpha is a dimerization partner.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A & M University, College Station, TX 77843, USA.
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Gu
authors.forename: Sui
authors.initials: S
authors.lastname: Ke
authors.forename: Duan
authors.initials: D
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Sheng
authors.forename: Paul E
authors.initials: PE
authors.lastname: Thomas
authors.forename: Arnold B
authors.initials: AB
authors.lastname: Rabson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.forename: Yanan
authors.initials: Y
authors.lastname: Tian
mesh_terms: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D019281:Dimerization; D015536:Down-Regulation / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000737:chemistry / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D008070:Lipopolysaccharides; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human