Data/hora: 13/06/2024 02:10:07

Provedor de dados: | 17
País: | United Kingdom
Título: | Hexose-6-phosphate dehydrogenase modulates the effect of inhibitors and alternative substrates of 11[beta]-hydroxysteroid dehydrogenase 1
Autores: | Zolt&amp;#xe1;n Bal&amp;#xe1;zs; Lyubomir G. Nashev; Charlie Chandsawangbhuwana; Michael E. Baker; Alex Odermatt.
Data: | 2008-10-22
Ano: | 2008
Palavras-chave: | Molecular Cell Biology; Pharmacology; Bioinformatics.
Resumo: | Intracellular glucocorticoid reactivation is catalyzed by 11[beta]-hydroxysteroid dehydrogenase 1 (11[beta]-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 11[beta]-HSD1 and very much depend on co-expression with H6PDH, providing cosubstrate NADPH. Here, we investigated the impact of H6PDH on the modulation of 11[beta]-HSD1-dependent inter-conversion of cortisone and cortisol by inhibitors and alternative substrates. Using HEK-293 cells expressing 11[beta]-HSD1 or co-expressing 11[beta]-HSD1 and H6PDH, we observed significant differences of 11[beta]-HSD1 inhibition by natural and pharmaceutical compounds as well as endogenous hormone metabolites. Furthermore, we show potent and dose-dependent inhibition of 11[beta]-HSD1 by 7-keto-DHEA in differentiated human THP-1 macrophages and in HEK-293 cells over-expressing 11[beta]-HSD1 with or without H6PDH. In contrast, 7-ketocholesterol (7-KC) did not inhibit 11[beta]-HSD1 in HEK-293 cells, even in the presence of H6PDH, but inhibited 11[beta]-HSD1 reductase activity in differentiated THP-1 macrophages (IC~50~ = 8.1 +/- 0.9 [mu]M). 7-keto-DHEA but not 7-KC inhibited 11[beta]-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.
Tipo: | Manuscript

Identificador:

http://precedings.nature.com/documents/2430/version/1

oai:nature.com:10101/npre.2008.2430.1

http://hdl.handle.net/10101/npre.2008.2430.1

Fonte: | Nature Precedings
Fonte: | Creative Commons Attribution 3.0 License