Drug disposition is a highly regulated process in mammals. For example, the expression of genes encoding drug-transporting and drug-metabolizing proteins is induced by their substrates in liver and intestine. Recent research has shed new light on the molecular mechanism of this phenomenon. The pregnane X receptor (PXR) is a ligand-activated transcription factor that is expressed in liver and intestine. PXR coordinately regulates the drug-inducible expression of drug-transporting and drug-metabolizing proteins in liver and intestine. PXR binds to xenobiotic-response elements (XREs) in the promoters of its target genes as a heterodimer with the 9-cis-retinoic acid receptor (RXR). One extremely important PXR-target gene is the cytochrome P450 3A4 (CYP3A4) gene. CYP3A4 is primarily expressed in liver and intestine where it catalyzes the oxidative metabolism of nearly 60% of all clinically prescribed drugs. The hepatic expression of CYP3A4 and other PXR-target genes is rapidly suppressed in response to inflammatory cytokines, though the molecular basis of this repression is currently unknown. Repression of PXR-target gene expression occurs in people that undergo invasive surgery in response to inflammation, thereby producing altered pharmacokinetic properties of drugs in these patients. PXR is activated by a plethora of structurally diverse molecules including drugs, steroids, bile acids, and xenobiotics. Therefore, repression of PXR-target gene expression can produce potentially life-threatening drug-drug interactions. Thus, it is important to understand the molecular basis of the repression of PXR-target genes in order to predict and prevent the occurrence of drug interactions in post-operative patients. An alteration in the phosphorylation status of transcriptional regulatory proteins is a likely mechanism that mediates the repression of PXR-target gene expression following inflammation. The goals of these investigations are to (1) identify the sites of PXR phosphorylation following activation of specific cell signaling pathways, and (2) determine the effect of increased PXR phosphorylation on it's ability to (a) transactivate, (b) bind DNA, (c) translocate from the cytoplasm to the nucleus, and (d) interact with protein co-factors. Successful completion of these studies will allow us to determine the molecular basis of the repression of key drug metabolizing genes during the inflammatory response and provide increased opportunities to understand the xenobiotic response. These studies will provide additional insight into the regulation of drug disposition and drug-drug interaction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068443-03
Application #
7269246
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Serrano, Jose
Project Start
2005-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$249,963
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Staudinger, Jeff L; Xu, Chenshu; Biswas, Arunima et al. (2011) Post-translational modification of pregnane x receptor. Pharmacol Res 64:4-10
Hu, Gang; Xu, Chenshu; Staudinger, Jeff L (2010) Pregnane X receptor is SUMOylated to repress the inflammatory response. J Pharmacol Exp Ther 335:342-50
Staudinger, Jeff L; Xu, Chenshu; Cui, Yue J et al. (2010) Nuclear receptor-mediated regulation of carboxylesterase expression and activity. Expert Opin Drug Metab Toxicol 6:261-71
Lichti-Kaiser, Kristin; Xu, Chenshu; Staudinger, Jeff L (2009) Cyclic AMP-dependent protein kinase signaling modulates pregnane x receptor activity in a species-specific manner. J Biol Chem 284:6639-49
Lichti-Kaiser, Kristin; Brobst, Dan; Xu, Chenshu et al. (2009) A systematic analysis of predicted phosphorylation sites within the human pregnane X receptor protein. J Pharmacol Exp Ther 331:65-76
Lichti-Kaiser, Kristin; Staudinger, Jeff L (2008) The traditional Chinese herbal remedy tian xian activates pregnane X receptor and induces CYP3A gene expression in hepatocytes. Drug Metab Dispos 36:1538-45
Staudinger, Jeff L; Lichti, Kristin (2008) Cell signaling and nuclear receptors: new opportunities for molecular pharmaceuticals in liver disease. Mol Pharm 5:17-34
Staudinger, Jeff L; Ding, Xunshan; Lichti, Kristin (2006) Pregnane X receptor and natural products: beyond drug-drug interactions. Expert Opin Drug Metab Toxicol 2:847-57
Ding, Xunshan; Lichti, Kristin; Kim, Insook et al. (2006) Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha. J Biol Chem 281:26540-51
Ding, Xunshan; Lichti, Kristin; Staudinger, Jeff L (2006) The mycoestrogen zearalenone induces CYP3A through activation of the pregnane X receptor. Toxicol Sci 91:448-55