title: Screening of a chemical library reveals novel PXR-activating pharmacologic compounds.
abstract: The pregnane X receptor (PXR) is one of the master regulators of xenobiotic transformation. Interactions between pharmacologic compounds and PXR frequently result in drug-to-drug interactions, drug-induced hepatotoxicity, and the development of drug-resistant phenotypes in cancer cells. Potential PXR-mediated effects on drug metabolism can be predicted using high-throughput methods to detect PXR transactivation. We used the reporter cell line nhrtox-hepg2 to screen an 1120-compound library of pharmacologic substances. Using a three-stage screening process combined with a quantitative structure-activity relationships (QSAR) analysis, we detected 16 novel, previously unreported PXR activators capable of upregulating CYP450 expression. For some of these compounds such as mycophenolic acid, leflunomide, and trifluridine, the observed interactions with PXR occurred at clinically significant concentrations and could provide potential mechanistic explanations for observed drug-to-drug interactions and drug-induced toxicity. A parallel QSAR analysis revealed significant correlation between the experimentally measured PXR-dependent bioactivity and the calculated molecular descriptors of the PXR activators.
authors.affiliation: Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Ratajewski
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University in Poznań, Umultowska 89b, 61-614 Poznań, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Grzelak
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University in Poznań, Umultowska 89b, 61-614 Poznań, Poland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Wiśniewska
authors.affiliation: Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Ryba
authors.affiliation: Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Gorzkiewicz
authors.affiliation: Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Walczak-Drzewiecka
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University in Poznań, Umultowska 89b, 61-614 Poznań, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland. Electronic address: jdastych@cbm.pan.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Dastych
mesh_terms: D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D065701:Cytochrome P-450 CYP3A Inducers / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D000077297:Pregnane X Receptor; D021281:Quantitative Structure-Activity Relationship; D011987:Receptors, Steroid / Q000819:agonists* / Q000378:metabolism; D054852:Small Molecule Libraries; D014162:Transfection
chemical_list: D065701:Cytochrome P-450 CYP3A Inducers; D008024:Ligands; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D054852:Small Molecule Libraries; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4; Chemical library; Drug to drug interaction; Etoposide; Leflunomide; Mycophenolic acid; PXR; QSAR; Trifluridine