Comparison of Gene Expression Patterns between 2,3,7,8-Tetrachlorodibenzo-p-dioxin and a Natural Arylhydrocarbon Receptor Ligand, Indirubin
| Autor: | Saburo Matsui, Tomonari Matsuda, Yoshitomo Mori, Jun Adachi |
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| Rok vydání: | 2004 |
| Předmět: |
Indoles
Insecta Polychlorinated Dibenzodioxins Time Factors Gene Expression In Vitro Techniques Ligands Toxicology chemistry.chemical_compound Cytochrome P-450 Enzyme System Cell Line Tumor Microsomes Gene expression Animals Humans heterocyclic compounds Receptor Dose-Response Relationship Drug biology Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling CYP1A2 Cytochrome P450 respiratory system Aryl hydrocarbon receptor Fold change Reverse transcription polymerase chain reaction Receptors Aryl Hydrocarbon chemistry Biochemistry biology.protein Indirubin |
| Zdroj: | Toxicological Sciences. 80:161-169 |
| ISSN: | 1096-0929 |
| DOI: | 10.1093/toxsci/kfh129 |
| Popis: | Indirubin is a natural arylhydrocarbon receptor (AhR) ligand isolated from human urine. We previously reported that it was more potent than the prototypical ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a yeast assay system. Here we compared gene expression changes in HepG2 cells exposed to 10 nM of indirubin or TCDD using nylon-membrane-based cDNA arrays with 1176 genes to elucidate the toxic differences at the transcriptional level. The gene expression profiles for TCDD and indirubin were very similar. The number of up-regulated genes (fold change > or =2.0) was 11 and 4 and the number of down-regulated genes (fold change < or =0.5) was 17 and 21 in TCDD-treated and indirubin-treated cells, respectively. Cytochrome P450 (CYP) 1A1, 1A2, 19A1, insulin-like growth factor binding protein 1 (IGFBP1), and IGFBP10 were confirmed to be up-regulated using real-time reverse transcription polymerase chain reaction. CYP1A1 and CYP1A2 mRNAs were induced by as little as 1 pM of indirubin, whereas they were not induced by 10 pM of TCDD. In the time-course experiment, CYP1A1 mRNA was induced by indirubin transiently. Indirubin was also metabolized by CYP1A1 and lost its ligand activity. Indirubin would appear to be a good substrate of CYP1A1 given its low dissociation constant. Our results suggest that indirubin rapidly activates its own metabolism via AhR-mediated induction of CYP1A1 and this characteristic is consistent with the notion that indirubin is a physiological ligand of AhR. |
| Databáze: | OpenAIRE |
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