Phosphorylation and protein–protein interactions in PXR-mediated CYP3A repression

Abstract

Background The expression of drug-metabolizing enzymes cytochrome P450 (CYPs) is controlled by pregnane X receptor (PXR), and therefore understanding how PXR modulates CYP expression is important to minimize adverse drug interactions, one type of preventable adverse drug reaction. Objective We review the mechanisms of PXR-mediated repression of CYP expression Methods We discuss the clinical implications of CYP repression and the role of signal cross-talks, including protein-protein interactions and phosphorylation of PXR and coregulators, in inhibiting PXR and repressing CYP expression Results/conclusion Kinases such as cyclin-dependent kinase 2 (Cdk2), protein kinase A (PKA), protein kinase C (PKC), and 70kDa form of ribosomal protein S6 kinase (p70 S6K) repress CYP expression by phosphorylating and inhibiting PXR. Growth factor signaling represses CYP expression by phosphorylating and inhibiting forkhead in rhabdomyosarcoma (FKHR), a coactivator of PXR. During inflammation, nuclear factor κB (NF-κB) represses both PXR and CYP expression via protein-protein interactions with the PXR pathway.

Protein Phosphatase 2Cβl Regulates Human Pregnane X Receptor-Mediated CYP3A4 Gene Expression in HepG2 Liver Carcinoma Cells

“…Hepatic CYP gene expression is affected by various signaling mechanisms, including reversible phosphorylation (Sidhu and Omiecinski, 1995;Marc et al, 2000;Pondugula et al, 2009a), and PXR-mediated CYP gene expression is modulated by both ligand binding and signaling crosstalk. We determined whether the phosphatase PP2C␤l affects hPXR transcriptional activity in HepG2 cells by measuring the activity of the PXR-regulated CYP3A4-luc reporter.…”

“…Recent studies demonstrated a role for phosphorylation-dependent signaling events in regulating PXR-mediated CYP gene expression (Pondugula et al, 2009a). Kinases such as protein kinase A (Ding and Staudinger, 2005a;Lichti-Kaiser et al, 2009), protein kinase C (Ding and Staudinger, 2005b), cyclin-dependent kinase (CDK)2 (Lin et al, 2008), and p70 ribosomal S6 kinase (Pondugula et al, 2009b) phosphorylate PXR and regulate PXR-mediated CYP gene expression.…”

“…Multiple research groups have established that CYP3A4 expression is significantly reduced in proliferating human liver cells (Pondugula et al, 2009a), strongly suggesting a link between cell cycle regulation and CYP3A4 expression. In fact, we have recently shown that CDK2 negatively regulates hPXR-mediated CYP3A4 gene expression in actively dividing HepG2 cells (Lin et al, 2008).…”

Synthesis and biological evaluation of 6H-1-benzopyrano[4,3-b]quinolin-6-one derivatives as inhibitors of colon cancer cell growth

“…Pglycoprotein) and ABCG2 (a.k.a. breast cancer esistance protein, BCRP) (Pondugula et al, 2009, Pondugula andMani, 2013). Activation of PXR by xenobiotics leads to chemoresistance, concern in drug development and clinical therapy.…”

Pregnane X Receptor in Drug Development

“…Post-translational regulation of Pregnane X Receptor 3.3.1 Phosphorylation Phosphorylation of PXR is often inhibitory (Pondugula et al 2009b). Treatment of primary rat and human hepatocytes with protein kinase A (PKA) activator leads to the attenuation of Cyp3A1 (Cyp3A1 is the rat ortholog of human CYP3A4) and CYP3A4 mRNA levels, respectively.…”