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Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-induced Suppression of Cytokine Production

Christel Gumy¹, Charlie Chandsawangbhuwana², Anna A. Dzyakanchuk¹, Denise V. Kratschmar¹, Michael E. Baker³ & Alex Odermatt¹

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1. Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
2. Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, U.S.A.
3. Department of Medicine, 0693 University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, U.S.A.

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Document Type:

Manuscript

Date:

Received 18 September 2008 19:55 UTC; Posted 19 September 2008

Subjects:

Immunology, Pharmacology, Bioinformatics

Tags:

• glucocorticoid receptor
• endocrine disruptor
• glucocorticoid
• tributyltin
• dibutyltin
• macrophage
• Organotin

Abstract:

Background. Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function.
Methodology. We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism.
Principal findings. We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-α-induced NF-κB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-α production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages.
Conclusions. DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Gumy, Christel, Chandsawangbhuwana, Charlie, Dzyakanchuk, Anna, Kratschmar, Denise, Baker, Michael, and Odermatt, Alex. Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-induced Suppression of Cytokine Production. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2008.2312.1> (2008)

Version info:

Published version:

10.1371/journal.pone.0003545 (Peer Reviewed) Published in PLoS ONE, 3(10).

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