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Selective inhibition of 11beta-hydroxysteroid dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid

Classen-Houben, D. and Schuster, D. and Da Cunha, T. and Odermatt, A. and Wolber, G. and Jordis, U. and Kueenburg, B.. (2009) Selective inhibition of 11beta-hydroxysteroid dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid. The journal of steroid biochemistry and molecular biology, Vol. 113, H. 3-5. pp. 248-252.

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Official URL: http://edoc.unibas.ch/dok/A5251922

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Abstract

Elevated cortisol concentrations have been associated with metabolic diseases such as diabetes type 2 and obesity. 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, catalyzing the conversion of inactive 11-ketoglucocorticoids into their active 11beta-hydroxy forms, plays an important role in the regulation of cortisol levels within specific tissues. The selective inhibition of 11beta-HSD1 is currently considered as promising therapeutic strategy for the treatment of metabolic diseases. In recent years, natural compound-derived drug design has gained considerable interest. 18beta-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin, is not selective and inhibits both 11beta-HSD1 and 11beta-HSD2. Here, we compare the biological activity of 18beta-GA and its diastereomer 18alpha-GA against the two enzymes in lysates of transfected HEK-293 cells and show that 18alpha-GA selectively inhibits 11beta-HSD1 but not 11beta-HSD2. This is in contrast to 18beta-GA, which preferentially inhibits 11beta-HSD2. Using a pharmacophore model based on the crystal structure of the GA-derivative carbenoxolone in complex with human 11beta-HSD1, we provide an explanation for the differences in the activities of 18alpha-GA and 18beta-GA. This model will be used to design novel selective derivatives of GA.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex and Da Cunha, Thierry
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Pergamon
ISSN:0960-0760
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:22 Mar 2012 14:19
Deposited On:22 Mar 2012 13:16

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