| Organotins Disrupt the 11β-Hydroxysteroid Dehydrogenase Type 2-Dependent Local Inactivation of Glucocorticoids Atanas G. Atanasov,1 Lyubomir G. Nashev,1 Steven Tam,2 Michael E. Baker,2 and Alex Odermatt1 1Department of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Berne, Switzerland; 2Department of Medicine, University of California, San Diego, La Jolla, California Abstract
Organotins, important environmental pollutants widely used in agricultural and industrial applications, accumulate in the food chain and induce imposex in several marine species as well as neurotoxic and immunotoxic effects in higher animals. Reduced birth weight and thymus involution, observed upon exposure to organotins, can also be caused by excessive glucocorticoid levels. We now demonstrate that organotins efficiently inhibit 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) , converting active 11β-hydroxyglucocorticoids into inactive 11-ketoglucocorticoids, but not 11β-HSD1, which catalyzes the reverse reaction. Di- and tributyltin as well as di- and triphenyltin inhibited recombinant and endogenous 11β-HSD2 in lysates and intact cells with IC50 values between 500 nM and 3 µM. Dithiothreitol protected 11β-HSD2 from organotin-dependent inhibition, indicating that organotins act by binding to one or more cysteines. Mutational analysis and 3-D structural modeling revealed several important interactions of cysteines in 11β-HSD2. Cys90, Cys228, and Cys264 were essential for enzymatic stability and catalytic activity, suggesting that disruption of such interactions by organotins leads to inhibition of 11β-HSD2. Enhanced glucocorticoid concentrations due to disruption of 11β-HSD2 function may contribute to the observed organotin-dependent toxicity in some glucocorticoid-sensitive tissues such as thymus and placenta. Key words: cortisol, dibutyltin, 11β-hydroxysteroid dehydrogenase, glucocorticoid, inhibition, organotin, toxicity, tributyltin, triphenyltin. Environ Health Perspect 113:1600-1606 (2005) . doi:10.1289/ehp.8209 available via http://dx.doi.org/ [Online 14 July 2005]
Address correspondence to A. Odermatt, Department of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland. Telephone: 41-31-632-9438. Fax: 41-31-632-9444. E-mail: alex.odermatt@dkf.unibe.ch We thank N. Farman (INSERM, Faculté X-Bichat, Paris, France) for providing the RCCD-2 cells, S. Andersson (University of Texas Southwestern Medical Center, Dallas, Texas) for the gift of 17β-HSD1 and 17β-HSD2 plasmids, and J. Vos (National Institute of Public Health and the Environment, Biltoven, the Netherlands) for helpful discussion. We also thank H. Jamin for excellent technical support. A.O. is a Cloëtta Research Fellow supported by grants from the Swiss National Science Foundation (3100A0-100060 and NRP50 "Endocrine Disruptors" 4050-066575) and the Swiss Cancer League (OCS-01402-08-2003) . M.E.B. and S.T. were supported by National Institute of Health grants DK41841 and HLOO4791. The authors declare they have no competing financial interests. Received 15 April 2005 ; accepted 14 July 2005.
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