Phosphorylation and protein-protein interactions in PXR-mediated CYP3A repression.
BACKGROUND
The expression of drug-metabolizing enzymes 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.


CONCLUSIONS
Kinases such as cyclin-dependent kinase 2, protein kinase A, PKC and 70 kDa form of ribosomal protein S6 kinase repress CYP expression by phosphorylating and inhibiting PXR. Growth factor signaling represses CYP expression by phosphorylating and inhibiting forkhead in rhabdomyosarcoma, a co-activator of PXR. During inflammation, NF-kappaB represses both PXR and CYP expression through protein-protein interactions with the PXR pathway.
Pondugula
Satyanarayana R
SR
St. Jude Children's Research Hospital, Department of Chemical Biology and Therapeutics, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, USA.
Dong
Hanqing
H
Chen
Taosheng
T
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects*; D000077297:Pregnane X Receptor; D011506:Proteins / Q000378:metabolism*; D011987:Receptors, Steroid / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D065692:Cytochrome P-450 CYP3A Inhibitors; D000077297:Pregnane X Receptor; D011506:Proteins; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A