PT  - JOURNAL ARTICLE
AU  - Sun-Hee Kim
AU  - Ellen C. Henry
AU  - Dong-Kyu Kim
AU  - Yun-Hee Kim
AU  - Kum Joo Shin
AU  - Myoung Sook Han
AU  - Taehoon G. Lee
AU  - Jong-Ku Kang
AU  - Thomas A. Gasiewicz
AU  - Sung Ho Ryu
AU  - Pann-Ghill Suh
TI  - Novel Compound 2-Methyl-2<em>H</em>-pyrazole-3-carboxylic Acid (2-methyl-4-<em>o</em>-tolylazo-phenyl)-amide (CH-223191) Prevents 2,3,7,8-TCDD-Induced Toxicity by Antagonizing the Aryl Hydrocarbon Receptor
AID  - 10.1124/mol.105.021832
DP  - 2006 Jun 01
TA  - Molecular Pharmacology
PG  - 1871--1878
VI  - 69
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/69/6/1871.short
4100  - http://molpharm.aspetjournals.org/content/69/6/1871.full
SO  - Mol Pharmacol2006 Jun 01; 69
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant with many toxic effects, including endocrine disruption, reproductive dysfunction, immunotoxicity, liver damage, and cancer. These are mediated by TCDD binding to and activating the aryl hydrocarbon receptor (AhR), a basic helix-loop-helix transcription factor. In this regard, targeting the AhR using novel small molecule inhibitors is an attractive strategy for the development of potential preventive agents. In this study, by screening a chemical library composed of approximately 10,000 compounds, we identified a novel compound, 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191), that potently inhibits TCDD-induced AhR-dependent transcription. In addition, CH-223191 blocked the binding of TCDD to AhR and inhibited TCDD-mediated nuclear translocation and DNA binding of AhR. These inhibitory effects of CH-223191 prevented the expression of cytochrome P450 enzymes, target genes of the AhR. Unlike many known antagonists of AhR, CH-223191 did not have detectable AhR agonist-like activity or estrogenic potency, suggesting that CH-223191 is a specific antagonist of AhR. It is noteworthy that CH-223191 potently prevented TCDD-elicited cytochrome P450 induction, liver toxicity, and wasting syndrome in mice. Taken together, these results demonstrate that this novel compound, CH-223191, may be a useful agent for the study of AhR-mediated signal transduction and the prevention of TCDD-associated pathology.