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NCOA6 differentially regulates the expression of the CYP2C9 and CYP3A4 genes.

CYP2Cs and CYP3A4 sub families of enzymes of the Cytochrome P450 super family metabolize clinically prescribed therapeutics. Constitutive and induced expressions of these enzymes are under the control of HNF4α and rifampicin activated PXR. In the present study, we show a mechanism for ligand dependent synergistic cross talk between PXR and HNF4α. Two-hybrid screening identified NCOA6 as a HNF4α interacting protein. NCOA6 was also found to interact with PXR through the first LXXLL motif in GST pull down and mammalian two hybrid assays. NCOA6 enhances the synergistic activation of CYP2C9 and CYP3A4 promoter activity by PXR and HNF4α in the presence of rifampicin. However silencing NCOA6 abrogated the synergistic activation and induction of CYP2C9 by PXR-HNF4α but not of CYP3A4. ChIP analysis revealed that NCOA6 could bridge HNF4α and PXR binding sites of the CYP2C9 promoter. Our results indicate that NCOA6 is responsible for the synergistic activation of CYP2C9 by HNF4α and PXR and NCOA6 differentially regulates CYP2C9 and CYP3A4 gene expression though both the genes are regulated by the same nuclear receptors.

Pubmed ID: 21292004

Authors

  • Surapureddi S
  • Rana R
  • Goldstein JA

Journal

Pharmacological research : the official journal of the Italian Pharmacological Society

Publication Data

May 25, 2011

Associated Grants

  • Agency: NIEHS NIH HHS, Id: Z01ES02124
  • Agency: Intramural NIH HHS, Id: ZIA ES021024-29

Mesh Terms

  • Aryl Hydrocarbon Hydroxylases
  • Chromatin Immunoprecipitation
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A
  • Gene Expression Regulation, Enzymologic
  • Hep G2 Cells
  • Hepatocyte Nuclear Factor 4
  • Humans
  • Nuclear Receptor Coactivators
  • Protein Interaction Mapping
  • Receptors, Steroid
  • Two-Hybrid System Techniques