The long-term goal of the proposed research is to study the transcriptional regulation of the phase II drug-metabolizing and clearing enzymes by the xenobiotic nuclear receptor PXR. The phase II conjugating enzymes such as the UDP-glucuronosyltransferases (UGTs) function in concert with the oxidative phase I cytochrome P450 enzymes (CYPs) to eliminate xenobiotics such as prescription drugs and over-the-counter medications, and endobiotics such as bilirubin, steroid hormones and bile acids. The nuclear receptor PXR was initially identified as a xenosensor to regulate the expression of CYP genes via its binding to the PXR-response elements found within the mammalian CYP gene promoters. The identity of PXR as a species-specific xenosensor has been established by previous transgenic and gene knockout studies. Having established CYP genes as PXR targets, the presence of candidate PXR response elements in genes encoding the phase II UGT gene products raises the potential for a broader physiological function of PXR in xenobiotic response and clearance. However, whether UGTs are induced by PXR is unclear. To investigate UGTs as potential transcriptional targets of PXR, we propose to: (1) clone the UGT1A1 promoter and characterize its regulation by PXR; (2) examine the regulation of hepatic UGTs in mouse models bearing heightened (VP-hPXR transgenic), compromised (PXR knockout), or """"""""humanized"""""""" (PXR knockout/hPXR transgenic) receptor activity; (3) examine the effect of altered PXR activity on bilirubin homeostasis; (4) examine the regulation of intestinal UGTs by PXR. If the regulation of phase II enzymes such as the UGTs by PXR proven to be true, we are toward establishing PXR as a master transcriptional regulator of the mammalian xenobiotic response. The results of these studies will provide novel elements in understanding the transcriptional regulation of UGT. It is anticipated that elucidation of the molecular basis of UGT regulation using the """"""""humanized"""""""" mice will have great implication in human physiology and diseases. These include bilirubin and hormonal homeostasis, drug metabolism, and chemical carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012479-02
Application #
6785260
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Thompson, Claudia L
Project Start
2003-08-01
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$295,267
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jiang, Mengxi; Xie, Wen (2013) Role of the constitutive androstane receptor in obesity and type 2 diabetes: a case study of the endobiotic function of a xenobiotic receptor. Drug Metab Rev 45:156-63
Chai, Xiaojuan; Zeng, Su; Xie, Wen (2013) Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond. Expert Opin Drug Metab Toxicol 9:253-66
Gao, Jie; Xie, Wen (2012) Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci 33:552-8
Ihunnah, Chibueze A; Jiang, Mengxi; Xie, Wen (2011) Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta 1812:956-63
He, Jinhan; Cheng, Qiuqiong; Xie, Wen (2010) Minireview: Nuclear receptor-controlled steroid hormone synthesis and metabolism. Mol Endocrinol 24:11-21
Ou, Zhimin; Huang, Min; Zhao, Lizi et al. (2010) Use of transgenic mice in UDP-glucuronosyltransferase (UGT) studies. Drug Metab Rev 42:123-31
Gao, Jie; He, Jinhan; Zhai, Yonggong et al. (2009) The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem 284:25984-92
Wada, Taira; Gao, Jie; Xie, Wen (2009) PXR and CAR in energy metabolism. Trends Endocrinol Metab 20:273-9
He, Jinhan; Xie, Wen (2009) Nuclear xenobiotic receptors: integrating gene regulation to physiological functions. Prog Mol Biol Transl Sci 87:87-116
Zhou, Jie; Febbraio, Maria; Wada, Taira et al. (2008) Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 134:556-67

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