Abstract
Dithiocarbamates (DTCs), important therapeutic and industrial chemicals released in high quantities into the environment, exhibit complex chemical and biological activities. Here, we demonstrate an effect of DTCs on glucocorticoid action due to inhibition of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, converting cortisol to cortisone in the kidney, but not 11β-HSD1, catalyzing the reverse reaction in liver and adipose tissue. Thus, DTCs may locally increase active glucocorticoid concentrations. Preincubation with the DTC thiram abolished 11β-HSD2 activity, suggesting irreversible enzyme inhibition. The sulfhydryl protecting reagent dithiothreitol blocked thiram-induced inhibition and NAD + partially protected 11β-HSD2 activity, indicating that DTCs act at the cofactor-binding site. A 3D-model of 11β-HSD2 identified Cys 90 in the NAD +-binding site as a likely target of DTCs, which was supported by a 99% reduced activity of mutant Cys 90 to serine. The interference of DTCs with glucocorticoid-mediated responses suggests a cautious approach in the use of DTCs in therapeutic applications and in exposure to sources of DTCs such as cosmetics and agricultural products by pregnant women and others.
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