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Hexose-6-phosphate dehydrogenase modulates the effect of inhibitors and alternative substrates of 11beta-hydroxysteroid dehydrogenase 1

Balazs, Z. and Nashev, L. G. and Chandsawangbhuwana, C. and Baker, M. E. and Odermatt, A.. (2009) Hexose-6-phosphate dehydrogenase modulates the effect of inhibitors and alternative substrates of 11beta-hydroxysteroid dehydrogenase 1. Molecular and cellular endocrinology, Vol. 301, H. 1-2. pp. 117-122.

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Official URL: http://edoc.unibas.ch/dok/A5251921

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Abstract

Intracellular glucocorticoid reactivation is catalyzed by 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), which functions predominantly as a reductase in cells expressing hexose-6-phosphate dehydrogenase (H6PDH). We recently showed that the ratios of cortisone to cortisol and 7-keto- to 7-hydroxy-neurosteroids are regulated by 11beta-HSD1 and very much depend on coexpression with H6PDH, providing cosubstrate NADPH. Here, we investigated the impact of H6PDH on the modulation of 11beta-HSD1-dependent interconversion of cortisone and cortisol by inhibitors and alternative substrates. Using HEK-293 cells expressing 11beta-HSD1 or coexpressing 11beta-HSD1 and H6PDH, we observed significant differences of 11beta-HSD1 inhibition by natural and pharmaceutical compounds as well as endogenous hormone metabolites. Furthermore, we show potent and dose-dependent inhibition of 11beta-HSD1 by 7-keto-DHEA in differentiated human THP-1 macrophages and in HEK-293 cells overexpressing 11beta-HSD1 with or without H6PDH. In contrast, 7-ketocholesterol (7-KC) did not inhibit 11beta-HSD1 in HEK-293 cells, even in the presence of H6PDH, but inhibited 11beta-HSD1 reductase activity in differentiated THP-1 macrophages (IC(50) 8.1+/-0.9muM). 7-Keto-DHEA but not 7-KC inhibited 11beta-HSD1 in HEK-293 cell lysates. In conclusion, cellular factors such as H6PDH can significantly modulate the effect of inhibitors and alternative 7-oxygenated substrates on intracellular glucocorticoid availability.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex and Balazs, Zoltan and Nashev, Lyubomir Georgiev
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0303-7207
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:22 Mar 2012 14:23
Deposited On:22 Mar 2012 13:33

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