ToxSci Advance Access originally published online on March 31, 2004
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Toxicological Sciences 80, 161-169 (2004)
Toxicological Sciences vol. 80 no. 1 © Society of Toxicology 2004; all rights reserved.
Comparison of Gene Expression Patterns between 2,3,7,8-Tetrachlorodibenzo-p-dioxin and a Natural Arylhydrocarbon Receptor Ligand, Indirubin
* Department of Technology and Ecology, Graduate School of Global Environmental Studies, Kyoto University, Kyoto, Japan, and Japanese Ministry of the Environment, Tokyo, Japan
Received December 26, 2003; accepted March 10, 2004
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 
2.0) was 11 and 4 and the number of down-regulated genes (fold change 
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.
Key Words: indirubin; AhR; TCDD; CYP1A1; metabolism; gene expression.
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