論文 - 詳細
| RRC ID | 44989 |
|---|---|
| 著者 | Imai J, Yamazoe Y, Yoshinari K. |
| タイトル | Novel cell-based reporter assay system using epitope-tagged protein for the identification of agonistic ligands of constitutive androstane receptor (CAR). |
| ジャーナル | Drug Metab Pharmacokinet |
| Abstract |
Constitutive androstane receptor (CAR) plays vital roles in multiple liver functions including xenobiotic and energy metabolisms, and also in hepatocarcinogenesis. CAR shows species-dependent ligand selectivity, leading to species differences in the actions of xenobiotics. Thus, to know whether a compound of interest activates human CAR or not is helpful for the chemical safety evaluation. However, it is very difficult to observe clear ligand response for CAR in cell-based assays, because of its high basal transcriptional activity in the absence of its ligands. In this study, we found that reporter assays using HepG2 cells human and mouse CAR fused with an epitope-tag at its C-terminus showed low basal activity and high response to the corresponding agonists but not to their indirect activator, phenobarbital. Using this system, 176 industrial chemicals were screened for their abilities to activate human and mouse CAR, and 6 compounds moderately or strongly activated human and/or mouse CAR. The CAR-mediated transcriptions induced by these compounds were blocked by clotrimazole or androstanol, the human and mouse CAR inverse agonists, respectively, suggesting that the newly identified CAR activators are agonistic ligands of CAR. Taken together, our reporter assay system may be a promising tool to assess chemicals' agonistic activities toward CAR. |
| 巻・号 | 28(4) |
| ページ | 290-8 |
| 公開日 | 2013-1-1 |
| DOI | 10.2133/dmpk.dmpk-12-rg-112 |
| PII | DN/JST.JSTAGE/dmpk/DMPK-12-RG-112 |
| PMID | 23268926 |
| MeSH | Androstanols / pharmacology Animals Aryl Hydrocarbon Hydroxylases / genetics Biological Assay Clotrimazole / pharmacology Constitutive Androstane Receptor Cytochrome P-450 CYP2B6 Epitopes / chemistry Hep G2 Cells Humans Ligands Liver / metabolism* Mice Phenobarbital / pharmacology RNA, Messenger / metabolism Receptors, Cytoplasmic and Nuclear / agonists* Receptors, Cytoplasmic and Nuclear / drug effects Species Specificity |
| IF | 42.779 |
| 引用数 | 876 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 7 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Hep G2 |