QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.013292v1 68/2/403    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mu, Y. Articles by Xie, W. Search for Related Content PubMed PubMed Citation Articles by Mu, Y. Articles by Xie, W.

A Pregnane X Receptor Agonist with Unique Species-Dependent Stereoselectivity and Its Implications in Drug Development

Center for Pharmacogenetics (Y.M., S.P.S.S., D.T., S.R., W.X.), Department of Pharmaceutical Sciences (Y.M., S.P.S.S., D.T., S.R., B.W.D., W.X.), Department of Chemistry (C.R.J.S., C.K., B.W.D., P.W.), Center for Chemical Methodologies and Library Development (C.R.J.S., C.K., P.W.), Department of Pathology (H.C., S.C.S.), and Department of Pharmacology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania

Pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of genes encoding drug-metabolizing enzymes and transporters. In addition to affecting drug metabolism, potent and selective PXR agonists may also have therapeutic potential by removing endogenous and exogenous toxins. In this article, we report the synthesis and identification of novel PXR agonists from a library of peptide isosteres. Compound S20, a C-cyclopropylalkylamide, was found to be a PXR agonist with both enantiomer- and species-specific selectivity. S20 has three chiral carbons and was resolved into its two enantiomers. The individual S20 enantiomers exhibited striking mouse/human-specific PXR activation, whereby enantiomer (+)-S20 preferentially activated hPXR, and enantiomer (-)-S20 was a better activator for mPXR. As a human PXR (hPXR) agonist, (+)-S20 was more potent and efficacious than rifampicin. Mutagenesis studies revealed that the ligand binding domain residue Phe305 is critical for the preference for the (-)-S20 enantiomer by the rodent PXR. Treatment of S20 induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays, in primary human hepatocytes, and in "humanized" hPXR transgenic mice. To our knowledge, S20 represents the first compound whose enantiomers have opposite species preference in activating a xenobiotic receptor. The stereoselectivity may be used to guide the development of safer drugs to avoid drug-drug interactions or to achieve human-specific therapeutic effects when a xenobiotic receptor is being used as a drug target.

Address correspondence to: Dr. Wen Xie, Center for Pharmacogenetics, Salk Hall 656, University of Pittsburgh, Pittsburgh, PA 15261. E-mail: wex6{at}pitt.edu

This article has been cited by other articles:

				T. Wada, H. S. Kang, M. Angers, H. Gong, S. Bhatia, S. Khadem, S. Ren, E. Ellis, S. C. Strom, A. M. Jetten, et al. Identification of Oxysterol 7{alpha}-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor {alpha} (ROR{alpha}) (NR1F1) Target Gene and a Functional Cross-Talk between ROR{alpha} and Liver X Receptor (NR1H3) Mol. Pharmacol., March 1, 2008; 73(3): 891 - 899. [Abstract] [Full Text] [PDF]

				A. Strasser, B. Striegl, H.-J. Wittmann, and R. Seifert Pharmacological Profile of Histaprodifens at Four Recombinant Histamine H1 Receptor Species Isoforms J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 60 - 71. [Abstract] [Full Text] [PDF]

				D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor Pharmacol. Rev., December 1, 2006; 58(4): 742 - 759. [Abstract] [Full Text] [PDF]

				J. Zhou, Y. Zhai, Y. Mu, H. Gong, H. Uppal, D. Toma, S. Ren, R. M. Evans, and W. Xie A Novel Pregnane X Receptor-mediated and Sterol Regulatory Element-binding Protein-independent Lipogenic Pathway J. Biol. Chem., May 26, 2006; 281(21): 15013 - 15020. [Abstract] [Full Text] [PDF]

				Y. Mu, J. Zhang, S. Zhang, H.-H. Zhou, D. Toma, S. Ren, L. Huang, M. Yaramus, A. Baum, R. Venkataramanan, et al. Traditional Chinese Medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) Activate Pregnane X Receptor and Increase Warfarin Clearance in Rats J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1369 - 1377. [Abstract] [Full Text] [PDF]

				H. Gong, S. V. Singh, S. P. Singh, Y. Mu, J. H. Lee, S. P. S. Saini, D. Toma, S. Ren, V. E. Kagan, B. W. Day, et al. Orphan Nuclear Receptor Pregnane X Receptor Sensitizes Oxidative Stress Responses in Transgenic Mice and Cancerous Cells Mol. Endocrinol., February 1, 2006; 20(2): 279 - 290. [Abstract] [Full Text] [PDF]