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Abstract
Grant Number: 5F05AT002029-03 Project Title: Traditional Chinese Medicines/Ligands/PXR punctuation.
PI Information: Name Title MU, YING yim1@pitt.edu Abstract: DESCRIPTION (provided by applicant): 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.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
Chinese, alternative medicine, cytochrome P450, enzyme induction /repression, ligand, nuclear receptor, pregnane compound
drug /agent, gene expression, liver cell, pharmacokinetics
gene targeting, genetically modified animal, high performance liquid chromatography, histochemistry /cytochemistry, laboratory mouse, northern blotting, tissue /cell culture, western blotting
Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH 350 THACKERAY HALL PITTSBURGH, PA 15260 Fiscal Year: 2005 Department: PHARMACEUTICAL SCIENCES Project Start: 30-SEP-2003 Project End: 31-AUG-2006 ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE IRG: ZAT1