NCOA6 differentially regulates the expression of the CYP2C9 and CYP3A4 genes

Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709, United States.
Pharmacological Research (Impact Factor: 4.41). 02/2011; 63(5):405-13. DOI: 10.1016/j.phrs.2011.01.013
Source: PubMed


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.

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    • "The four subfamilies of CYP are involved in different drug-metabolism processes, and both CYP2C9 and cytochrome P450 2C19 (CYP2C19) have major clinical functions [2]. CYP2C9 can metabolize a large range of therapeutic drugs, such as those involved with blood sugar regulation, anticoagulants, and the weak acid or base types of drugs [3–5]. CYP2C9 is involved in an NADPH-dependent electron transport pathway in liver microsomes [6]. "
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    • "They are found at highest levels in human liver (Goldstein and de Morais, 1994; Inoue et al., 1994; Klose et al., 1999; Nishimura et al., 2003), but CYP2C protein and/or mRNA expression has been detected at lower levels in extrahepatic tissues such as kidney, lung, heart, endothelial tissue, adrenal gland, mammary gland, and brain (McFayden et al., 1998; Klose et al., 1999; Nishimura et al., 2003; Yasar et al., 2003; Delozier et al., 2007; Deng et al., 2011). Numerous studies have described the transcriptional upregulation of CYP2C genes by xenobiotics (Pascussi et al., 2000a; Ferguson et al., 2002; Chen et al., 2004), including clinically prescribed and nonprescription drugs such as phenobarbital , rifampicin, St. John's wort, and dexamethasone, through the xenobiotic-sensing receptors constitutive androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR) (Ferguson et al., 2002; Chen et al., 2003a, 2004; Rana et al., 2010, 2011; Surapureddi et al., 2011). The CYP2C genes are also up-regulated by the liverenriched receptor hepatic nuclear factor 4␣ (HNF4␣) (Ferguson et al., 2005; Rana et al., 2010; Yue et al., 2010). "
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