Journal Article

The Novel Antibacterial Compound Walrycin A Induces Human PXR Transcriptional Activity

Alexandre Berthier, Frédérik Oger, Céline Gheeraert, Abdel Boulahtouf, Rémy Le Guével, Patrick Balaguer, Bart Staels, Gilles Salbert and Philippe Lefebvre

in Toxicological Sciences

Volume 127, issue 1, pages 225-235
Published in print May 2012 | ISSN: 1096-6080
Published online February 2012 | e-ISSN: 1096-0929 | DOI:
The Novel Antibacterial Compound Walrycin A Induces Human PXR Transcriptional Activity

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The human pregnane X receptor (PXR) is a ligand-regulated transcription factor belonging to the nuclear receptor superfamily. PXR is activated by a large, structurally diverse, set of endogenous and xenobiotic compounds and coordinates the expression of genes central to metabolism and excretion of potentially harmful chemicals and therapeutic drugs in humans. Walrycin A is a novel antibacterial compound targeting the WalK/WalR two-component signal transduction system of Gram (+) bacteria. Here, we report that, in hepatoma cells, walrycin A potently activates a gene set known to be regulated by the xenobiotic sensor PXR. Walrycin A was as efficient as the reference PXR agonist rifampicin to activate PXR in a transactivation assay at noncytotoxic concentrations. Using a limited proteolysis assay, we show that walrycin A induces conformational changes at a concentration which correlates with walrycin A ability to enhance the expression of prototypic target genes, suggesting that walrycin A interacts with PXR. The activation of the canonical human PXR target gene CYP3A4 by walrycin A is dose and PXR dependent. Finally, in silico docking experiments suggest that the walrycin A oxidation product Russig’s blue is the actual ligand for PXR. Taken together, these results identify walrycin A as a novel human PXR activator.

Keywords: walrycin A; pregnane X receptor; nuclear receptor; CYP3A4; ligand-binding domain; xenobiotic

Journal Article.  6157 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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