The long-term objective of the project is to elucidate the molecular basis for herb-drug interactions, and to develop molecular-based technologies to predict such interactions. The major objective of this project is to reveal molecular details involving the activation of the pregnane X receptor (PXR) by Chinese herbal extracts and model compounds hyperforin and guggulsterone. The model compounds represent the most used herbal supplements, and are shown to activate PXR. Activation of this receptor markedly induces the expression of drug-metabolizing enzymes, resulting in severe herb-drug interactions. PXR is a member of the nuclear receptor superfamily, and recruits very same coactivators as other nuclear receptors. Interestingly, hyperforin is more potent toward human PXR, whereas guggulsterone is more potent toward rodent PXRs. The goals of this project are: (1) to determine the structural basis for the species-preferable activation; (2) to determine whether Chinese herbal extracts, known to induce drug-metabolizing enzymes, activate PXR; (3) to determine whether depletion of coactivators reduces hyperforin-mediated activation of PXR; and (4) to provide the applicant with a much-needed exercise on high-end molecular techniques. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
International Research Fellowships (FIC) (F05)
Project #
5F05AT003019-02
Application #
7108583
Study Section
Special Emphasis Panel (ZAT1-LD (01))
Program Officer
Hayes, Deborah
Project Start
2005-08-01
Project End
2010-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$61,036
Indirect Cost
Name
University of Rhode Island
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
144017188
City
Kingston
State
RI
Country
United States
Zip Code
02881
Yang, Dongfang; Yang, Jian; Shi, Deshi et al. (2012) Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of carboxylesterase and bile salt export pump. J Lipid Res 53:529-39
Peng, Yan; Liu, Wei; Xiong, Jing et al. (2012) Down regulation of differentiated embryonic chondrocytes 1 (DEC1) is involved in 8-methoxypsoralen-induced apoptosis in HepG2 cells. Toxicology 301:58-65
Zhao, Mao; Xiaofei, Luan; Gang, Cao et al. (2012) DEC1 binding to the proximal promoter of CYP3A4 ascribes to the downregulation of CYP3A4 expression by IL-6 in primary human hepatocytes. Biochem Pharmacol 84:701-711
Feng, Xue-Min; Xiong, Jing; Qin, Hao et al. (2012) Fluoxetine induces hepatic lipid accumulation via both promotion of the SREBP1c-related lipogenesis and reduction of lipolysis in primary mouse hepatocytes. CNS Neurosci Ther 18:974-80
Mao, Zhao; Li, Yang; Peng, Yan et al. (2011) Lipopolysaccharide down-regulates carbolesterases 1 and 2 and reduces hydrolysis activity in vitro and in vivo via p38MAPK-NF-?B pathway. Toxicol Lett 201:213-20
Yang, Jian; Luan, Xiaofei; Gui, Haiyan et al. (2011) Byakangelicin induces cytochrome P450 3A4 expression via transactivation of pregnane X receptors in human hepatocytes. Br J Pharmacol 162:441-51
Yang, Dongfang; Yang, Jian; Shi, Deshi et al. (2011) Scoparone potentiates transactivation of the bile salt export pump gene and this effect is enhanced by cytochrome P450 metabolism but abolished by a PKC inhibitor. Br J Pharmacol 164:1547-57
Hao, Chunshu; Liu, Wei; Luan, Xiaofei et al. (2010) Aquaporin-4 knockout enhances astrocyte toxicity induced by 1-methyl-4-phenylpyridinium ion and lipopolysaccharide via increasing the expression of cytochrome P4502E1. Toxicol Lett 198:225-31
Yang, Jian; Hao, Chunshu; Yang, Dongfang et al. (2010) Pregnane X receptor is required for interleukin-6-mediated down-regulation of cytochrome P450 3A4 in human hepatocytes. Toxicol Lett 197:219-26
Shi, Deshi; Yang, Jian; Yang, Dongfang et al. (2008) Dexamethasone suppresses the expression of multiple rat carboxylesterases through transcriptional repression: evidence for an involvement of the glucocorticoid receptor. Toxicology 254:97-105

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