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Species-specific differences in the inhibition of human and zebrafish 11β-hydroxysteroid dehydrogenase 2 by thiram and organotins

Meyer, Arne and Strajhar, Petra and Murer, Céline and Da Cunha, Thierry and Odermatt, Alex. (2012) Species-specific differences in the inhibition of human and zebrafish 11β-hydroxysteroid dehydrogenase 2 by thiram and organotins. Toxicology, Vol. 301, H. 1-3. pp. 72-78.

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Official URL: http://edoc.unibas.ch/dok/A6070437

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Abstract

Dithiocarbamates and organotins can inhibit enzymes by interacting with functionally essential sulfhydryl groups. Both classes of chemicals were shown to inhibit human 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), which converts active cortisol into inactive cortisone and has a role in renal and intestinal electrolyte regulation and in the feto-placental barrier to maternal glucocorticoids. In fish, 11β-HSD2 has a dual role by inactivating glucocorticoids and generating the major androgen 11-ketotestosterone. Inhibition of this enzyme may enhance glucocorticoid and diminish androgen effects in fish. Here, we characterized 11β-HSD2 activity of the model species zebrafish. A comparison with human and mouse 11β-HSD2 revealed species-specific substrate preference. Unexpectedly, assessment of the effects of thiram and several organotins on the activity of zebrafish 11β-HSD2 showed weak inhibition by thiram and no inhibition by any of the organotins tested. Sequence comparison revealed the presence of an alanine at position 253 on zebrafish 11β-HSD2, corresponding to cysteine-264 in the substrate-binding pocket of the human enzyme. Substitution of alanine-253 by cysteine resulted in a more than 10-fold increased sensitivity of zebrafish 11β-HSD2 to thiram. Mutating cysteine-264 on human 11β-HSD2 to serine resulted in 100-fold lower inhibitory activity. Our results demonstrate significant species differences in the sensitivity of human and zebrafish 11β-HSD2 to inhibition by thiram and organotins. Site-directed mutagenesis revealed a key role of cysteine-264 in the substrate-binding pocket of human 11β-HSD2 for sensitivity to sulfhydryl modifying agents.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex and Meyer, Arne and Da Cunha, Thierry
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0300-483X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Mar 2013 11:14
Deposited On:01 Mar 2013 11:12

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