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Originally published In Press as doi:10.1074/jbc.C100238200 on June 25, 2001

J. Biol. Chem., Vol. 276, Issue 34, 31475-31478, August 24, 2001
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ACCELERATED PUBLICATION
Indirubin and Indigo Are Potent Aryl Hydrocarbon Receptor Ligands Present in Human Urine*

Jun AdachiDagger , Yoshitomo MoriDagger , Saburo MatsuiDagger , Hidetaka Takigami§, Junko Fujino§, Hiroko Kitagawa§, Charles A. Miller III||, Takaaki Kato**, Kenichi Saeki**, and Tomonari Matsuda§Dagger Dagger

From the Dagger  Department of Environmental Engineering, Kyoto University, Sakyo-Ku, Yoshida-Honmachi, Kyoto 606-8501, Japan, § Research Center for Environmental Quality Control, Kyoto University, 1-2 Yumihama, Otsu 520-0811, Japan,  Department of Environmental Health Sciences and Tulane-Xavier Center for Bioenvironmental Research, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana 70112, and ** Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabedori, Mizuho-ku, Nagoya 467-8603, Japan

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates genes involved in xenobiotic metabolism, cellular proliferation, and differentiation. Numerous xenobiotic and biological compounds are known to interact with AhR, but it remains an orphan receptor, because its physiological ligand is unknown. We identified AhR ligands in human urine using a yeast AhR signaling assay and then characterized their properties. Two ligands, indirubin and indigo, were both present at average concentrations of ~0.2 nM in the urine of normal donors. Indirubin was also detected in fetal bovine serum and contributed half of the total AhR ligand activity. The activities of indirubin and indigo were comparable with or more potent than that of the archetypal ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, in yeast AhR activation assays. We suggest that the endogenous levels and potencies of indirubin and indigo are such that they activate AhR-mediated signaling mechanisms in vivo.

* This work was supported in part by Grants-in-aid for Scientific Research 11750490, 12055101, and 12771444 from the Japanese Ministry of Education, Science, Sports and Culture, by the Fundamental Research Fund for the Environmental Future ("Assessment and Control of Risks to Progeny from Exposure to Complex Chemicals in the Environment") from the Japanese Ministry of the Environment, and by National Institutes of Health Grant ES09055.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom requests for the yeast strain should be addressed. Tel.: 504-585-6942; Fax: 504-585-6942; E-mail: rellim@tulane.edu.

Dagger Dagger To whom correspondence should be addressed. Tel.: 81-77-527-6224; Fax: 81-77-524-9869; E-mail: matsuda@biwa.eqc.kyoto-u.ac.jp.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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