Comparison of gene expression patterns between 2,3,7,8-tetrachlorodibenzo-p-dioxin and a natural arylhydrocarbon receptor ligand, indirubin.
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Adachi J, Mori Y, Matsui S, Matsuda T
Comparison of gene expression patterns between 2,3,7,8-tetrachlorodibenzo-p-dioxin and a natural arylhydrocarbon receptor ligand, indirubin.
Toxicol Sci. 2004 Jul;80(1):161-9. Epub 2004 Mar 31.
- PubMed ID
- 15056799 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Indirubin Aryl hydrocarbon receptor Protein Humans UnknownAgonistDetails Indirubin Cytochrome P450 1A1 Protein Humans UnknownSubstrateDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Indirubin Investigational ACADSB 36 downregulated indirubin results in decreased expression of ACADSB mRNA 10q26.13 Indirubin Investigational ARF4 378 downregulated indirubin results in decreased expression of ARF4 mRNA 3p14.3 Indirubin Investigational CCT4 10575 downregulated indirubin results in decreased expression of CCT4 mRNA 2p15 Indirubin Investigational CDH2 1000 downregulated indirubin results in decreased expression of CDH2 mRNA 18q12.1 Indirubin Investigational CDK1 983 downregulated indirubin results in decreased expression of CDK1 mRNA 10q21.2 Indirubin Investigational CLK1 1195 downregulated indirubin results in decreased expression of CLK1 mRNA 2q33.1 Indirubin Investigational COPS2 9318 downregulated indirubin results in decreased expression of COPS2 mRNA 15q21.2 Indirubin Investigational CYP19A1 1588 upregulated indirubin results in increased expression of CYP19A1 mRNA 15q21.2 Indirubin Investigational CYP1A1 1543 upregulated indirubin results in increased expression of CYP1A1 mRNA 15q24.1 Indirubin Investigational CYP1A2 1544 upregulated indirubin results in increased expression of CYP1A2 mRNA 15q24.1 Indirubin Investigational CYR61 3491 upregulated indirubin results in increased expression of CYR61 mRNA 1p22.3 Indirubin Investigational E2F1 1869 downregulated indirubin results in decreased expression of E2F1 mRNA 20q11.22 Indirubin Investigational GSTP1 2950 upregulated indirubin results in increased expression of GSTP1 mRNA 11q13.2 Indirubin Investigational HSBP1 3281 downregulated indirubin results in decreased expression of HSBP1 mRNA 16q23.3 Indirubin Investigational HSPD1 3329 downregulated indirubin results in decreased expression of HSPD1 mRNA 2q33.1 Indirubin Investigational HSPH1 10808 downregulated indirubin results in decreased expression of HSPH1 mRNA 13q12.3 Indirubin Investigational IGFBP1 3484 upregulated indirubin results in increased expression of IGFBP1 mRNA 7p12.3 Indirubin Investigational IL1R1 3554 downregulated indirubin results in decreased expression of IL1R1 mRNA 2q11.2-q12.1 Indirubin Investigational ILF2 3608 downregulated indirubin results in decreased expression of ILF2 mRNA 1q21.3 Indirubin Investigational ITGB1 3688 downregulated indirubin results in decreased expression of ITGB1 mRNA 10p11.22 Indirubin Investigational MGST2 4258 downregulated indirubin results in decreased expression of MGST2 mRNA 4q31.1 Indirubin Investigational MSH2 4436 downregulated indirubin results in decreased expression of MSH2 mRNA 2p21-p16.3 Indirubin Investigational NPC1 4864 upregulated indirubin results in increased expression of NPC1 mRNA 18q11.2 Indirubin Investigational SEPT2 4735 downregulated indirubin results in decreased expression of SEPT2 mRNA 2q37.3 Indirubin Investigational SLC2A2 6514 downregulated indirubin results in decreased expression of SLC2A2 mRNA 3q26.2 Indirubin Investigational TCF12 6938 downregulated indirubin results in decreased expression of TCF12 mRNA 15q21.3 Indirubin Investigational TOP1 7150 downregulated indirubin results in decreased expression of TOP1 mRNA 20q12 Indirubin Investigational TOP2A 7153 downregulated indirubin results in decreased expression of TOP2A mRNA 17q21.2 Isatin Experimental CYP2A6 1548 upregulated Isatin results in increased expression of CYP2A6 mRNA 19q13.2 Isatin Experimental CYP2D6 1565 upregulated Isatin results in increased expression of CYP2D6 mRNA 22q13.2 Isatin Experimental CYP2E1 1571 upregulated Isatin results in increased expression of CYP2E1 mRNA 10q26.3