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

• Published in: Molecular and cellular endocrinology Vol. 301; no. 1; pp. 117 - 122
• Main Authors: Balázs, Zoltán, Nashev, Lyubomir G., Chandsawangbhuwana, Charlie, Baker, Michael E., Odermatt, Alex
• Format: Journal Article
• Language: English
• Published: Elsevier Ireland Ltd 25.03.2009
• Subjects: 11β-Hydroxysteroid dehydrogenase; 7-Ketocholesterol; Cellular; Cortisone; DHEA; Glucocorticoid; Glucocorticoids; Hexose-6-phosphate dehydrogenase; Inhibition; Inhibitors; Macrophages; Oxysterol; Reductases; Substrate inhibition; DHEA; Hexose-6-phosphate dehydrogenase; H6PDH; 7-KC; 11β-Hydroxysteroid dehydrogenase; Oxysterol; 11β-HSD; TLC; 7β-OHC; 7-Ketocholesterol; ER; Glucocorticoid
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2008.10.021

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 coexpression with H6PDH, providing cosubstrate NADPH. Here, we investigated the impact of H6PDH on the modulation of 11β-HSD1-dependent interconversion of cortisone and cortisol by inhibitors and alternative substrates. Using HEK-293 cells expressing 11β-HSD1 or coexpressing 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 overexpressing 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 (IC 50 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.