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Novel Compound 2-Methyl-2H-pyrazole-3-carboxylic Acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) Prevents 2,3,7,8-TCDD-Induced Toxicity by Antagonizing the Aryl Hydrocarbon Receptor

School of Environmental Science and Engineering (S.-H.K., K.J.S., S.H.R., P.-G.S.), Department of Life Science (Y.-H.K., S.H.R., P.-G.S.), SIGMOL Inc. (M.S.H., T.G.L.), Pohang University of Science and Technology, Pohang, South Korea; Department of Laboratory Animal Medicine College of Veterinary Medicine, Chungbuk National University, Cheongju Chungbuk, South Korea (D.-K.K., J.-K.K.); and Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, New York (E.C.H., T.A.G.)

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.

Received for publication December 19, 2005.

Accepted for publication March 15, 2006.

Address correspondence to: Pann-Ghill Suh, School of Environmental Science and Engineering, Department of Life Science, Division of Molecular and Life Science, and, Pohang University of Science and Technology, Pohang, 790-784, South Korea. E-mail: pgs{at}postech.ac.kr

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