Use of comprehensive screening methods to detect selective human CAR activators
| Autor: | Ferdinand Molnár, Timo Rousu, Paavo Honkakoski, Tobias Abel, Ari Tolonen, Timo Korjamo, Tanja Kortelainen, Johanna Jyrkkärinne, Tuomo Laitinen, Jouko Uusitalo, Jenni Küblbeck |
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| Rok vydání: | 2011 |
| Předmět: |
Agonist
Receptors Steroid medicine.drug_class Receptors Cytoplasmic and Nuclear Computational biology Pharmacology Biology Biochemistry Gene Expression Regulation Enzymologic Small Molecule Libraries Cytochrome P-450 Enzyme System Cell Line Tumor Constitutive androstane receptor medicine Basic Helix-Loop-Helix Transcription Factors Humans Receptor Gene Constitutive Androstane Receptor Pregnane X receptor Dose-Response Relationship Drug Molecular Structure Pregnane X Receptor Reproducibility of Results Aryl hydrocarbon receptor Drug development Receptors Aryl Hydrocarbon biology.protein Hepatocytes Function (biology) Protein Binding |
| Zdroj: | Biochemical pharmacology. 82(12) |
| ISSN: | 1873-2968 |
| Popis: | The so-called human xenosensors, constitutive androstane receptor (hCAR), pregnane X receptor (hPXR) and aryl hydrocarbon receptor (hAhR), participate in drug metabolism and transport as well as in several endogenous processes by regulating the expression of their target genes. While the ligand specificities for hPXR and hAhR are relatively well described, this property of hCAR still remains fairly unclear. Identifying hCAR agonists for drug development and for studying hCAR biology are hindered mainly by the unique properties of the receptor, such as the high constitutive activity and complex signaling network but also by the lack of robust and reliable assays and cellular models. Here, validated reporter assays for these three xenosensors are presented and thereafter used to screen a large set of chemicals in order to find novel selective hCAR ligands. We introduce a novel selective hCAR agonist, FL81, which can be used as a stable positive control in hCAR activity assays. Our established receptor-selective ligand identification methods consisting of supporting biological assays and molecular modeling techniques are then used to study FL81 as well as other discovered ligands, such as diethylstilbestrol, o,p′-DDT, methoxychlor and permethrin, for their ability to specifically activate hCAR and to regulate the CYP enzyme expression and function. |
| Databáze: | OpenAIRE |
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