Inhibition of 11 beta-hydroxysteroid dehydrogenase type 2 by dithiocarbamates.
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 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 2, converting cortisol to cortisone in the kidney, but not 11 beta-HSD1, catalyzing the reverse reaction in liver and adipose tissue. Thus, DTCs may locally increase active glucocorticoid concentrations. Preincubation with the DTC thiram abolished 11 beta-HSD2 activity, suggesting irreversible enzyme inhibition. The sulfhydryl protecting reagent dithiothreitol blocked thiram-induced inhibition and NAD+ partially protected 11 beta-HSD2 activity, indicating that DTCs act at the cofactor-binding site. A 3D-model of 11 beta-HSD2 identified Cys90 in the NAD(+)-binding site as a likely target of DTCs, which was supported by a 99% reduced activity of mutant Cys90 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.
Atanasov
Atanas G
AG
Division of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Berne CH-3010, Switzerland.
Tam
Steven
S
Röcken
Jens M
JM
Baker
Michael E
ME
Odermatt
Alex
A
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D019943:Amino Acid Substitution; D020134:Catalytic Domain / Q000235:genetics; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry; D004785:Environmental Pollutants / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D009243:NAD / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D013859:Thiocarbamates / Q000737:chemistry / Q000633:toxicity*; D013893:Thiram / Q000494:pharmacology / Q000633:toxicity; D014162:Transfection
D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013859:Thiocarbamates; D013893:Thiram; D009243:NAD; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D003545:Cysteine