Journal
ENVIRONMENTAL HEALTH PERSPECTIVES
Volume 113, Issue 11, Pages 1600-1606Publisher
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
DOI: 10.1289/ehp.8209
Keywords
cortisol; dibutyltin; 11 beta-hydroxysteroid dehydrogenase; glucocorticoid; inhibition; organotin; toxicity; tributyltin; triphenyltin
Funding
- NHLBI NIH HHS [HL004791] Funding Source: Medline
- NIDDK NIH HHS [R01 DK041841, DK41841] Funding Source: Medline
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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 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2), converting active 11 beta-hydroxyglucocorticoids into inactive 11-ketoglucocorticoids, but not 11 beta-HSD1, which catalyzes the reverse reaction. Di- and tributyltin as well as di- and triphenyltin inhibited recombinant and endogenous 11 beta-HSD2 in lysates and intact cells with IC50 values between 500 nM and 3 mu M. Dithiothreitol protected 11 beta-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 11 beta-HSD2. Cys(90), Cys(228), and Cys(264) were essential for enzymatic stability and catalytic activity, suggesting that disruption of such interactions by organotins leads to inhibition of 11 beta-HSD2. Enhanced glucocorticoid concentrations due to disruption of 11 beta-HSD2 function may contribute to the observed organotin-dependent toxicity in some glucocorticoid-sensitive tissues such as thymus and placenta.
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