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

Zoltán Balázs¹, Lyubomir G. Nashev¹, Charlie Chandsawangbhuwana², Michael E. Baker² & Alex Odermatt¹

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1. Department of Pharmaceutical Sciences, University of Basel
2. Department of Medicine, University of California, San Diego

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Document Type:

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Date:

Received 22 October 2008 18:32 UTC; Posted 22 October 2008

Subjects:

Molecular Cell Biology, Pharmacology, Bioinformatics

Tags:

• glucocorticoid
• DHEA
• oxysterol
• Evolution
• 7-ketocholesterol
• hexose-6-phosphate
• structure-function
• 11β-hydroxysteroid dehydrogenase

Abstract:

Intracellular glucocorticoid reactivation is catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-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 11β-HSD1 and very much depend on co-expression with H6PDH, providing cosubstrate NADPH. Here, we investigated the impact of H6PDH on the modulation of 11β-HSD1-dependent inter-conversion of cortisone and cortisol by inhibitors and alternative substrates. Using HEK-293 cells expressing 11β-HSD1 or co-expressing 11β-HSD1 and H6PDH, we observed significant differences of 11β-HSD1 inhibition by natural and pharmaceutical compounds as well as endogenous hormone metabolites. Furthermore, we show potent and dose-dependent inhibition of 11β-HSD1 by 7-keto-DHEA in differentiated human THP-1 macrophages and in HEK-293 cells over-expressing 11β-HSD1 with or without H6PDH. In contrast, 7-ketocholesterol (7-KC) did not inhibit 11β-HSD1 in HEK-293 cells, even in the presence of H6PDH, but inhibited 11β-HSD1 reductase activity in differentiated THP-1 macrophages (IC₅₀ = 8.1 +/- 0.9 μM). 7-keto-DHEA but not 7-KC inhibited 11β-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.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Balázs, Zoltán, Nashev, Lyubomir, Chandsawangbhuwana, Charlie, Baker, Michael, and Odermatt, Alex. Hexose-6-phosphate dehydrogenase modulates the effect of inhibitors and alternative substrates of 11β-hydroxysteroid dehydrogenase 1. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2008.2430.1> (2008)

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