The traditional Chinese medicines (TCMs) are essential components of alternative medicine. Some TCMs, particularly those exhibit general detoxifying and hepato-protective activities, are known to induce hepatic cytochrome P450 (CYP) enzymes, such as the CYP3A isoenzymes. The molecular mechanism of the TCM-mediated CYP induction is largely unknown. Based on our preliminary results, we hypothesize that TCM induction of CYP3A is mediated by the xenobiotic nuclear receptor PXR (pregnane X receptor). Activation of PXR by TCMs triggers xenobiotic responses to induce CYP3A enzyme gene expression. To test these hypotheses, using combinations of cell cultures and transgenic mice, we propose to: 1) To determine whether TCMs are able to induce CYP3A enzymes in primary cultures of human hepatocytes; 2) To determine whether TCMs can induce CYP3A enzymes by activating the PXR. These will be determined by using transient transfection and CYP3A reporter gene assay; 3) To determine whether PXR activation by TCMs is a human-specific event; and 4) To determine whether TCMs induce CYP3A expression in vivo in the """"""""humanized"""""""" mice. The """"""""humanized"""""""" mice have the mouse PXR receptor genetically replaced by its human counterpart. Results of these studies will shed light on the mechanism of TCM induction of CYP enzymes. In our view, an understanding of the mechanisms underlying the CYP induction by TCMs will not only provide molecular explanation for therapeutic effects of certain TCMs, but also will guide the safer clinical use of TCMs.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
International Research Fellowships (FIC) (F05)
Project #
1F05AT002029-01
Application #
6742814
Study Section
Special Emphasis Panel (ZAT1-CP (08))
Program Officer
Pearson, Nancy
Project Start
2003-09-30
Project End
2008-09-29
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$60,808
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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