Role of NF- Kappa B in Regulation of PXR-mediated Gene Expression: A mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents

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- Kappa B activation by lipopolysaccharide and tumor necrosis factor- alpha plays a pivotal role in the suppression of cyp3a4 through interactions of NF- Kappa B with the PXR.retinoid X receptor (RXR) complex. Inhibition of NF- Kappa B by NF- Kappa B-specific suppressor SRI Kappa B alpha reversed the suppressive effects of lipopolysaccharide and tumor necrosis factor- alpha . Furthermore, we showed that NF- Kappa B p65 disrupted the association of the PXR.RXR alpha complex with DNA sequences as determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. NF- Kappa B p65 directly interacted with the DNA-binding domain of RXR alpha and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by the PXR.RXR alpha complex. This mechanism of suppression by NF- Kappa B activation may be extended to other nuclear receptor-regulated systems where RXR alpha is a dimerization partner.