The native anti-glucocorticoid paradigm

7α- and 7β-hydroxy-epiandrosterone as substrates and inhibitors for the human 11β-hydroxysteroid dehydrogenase type 1

“…On the other hand, and with regard to the EpiA derivatives studied here, the implications of our findings in the metabolic regulation of the 11␤-HSD1-mediated cortisol-cortisone oxido-reduction are dubious for the following reasons: (i) because of its conversion to the sulfate derivative, EpiA circulating levels in human adults are very low [17], and the K cat /K M ratio for its 7␣-hydroxylation is one order of magnitude lower than for DHEA [1]; (ii) the once produced 7␣-hydroxy-EpiA is rapidly excreted under sulfate form [18]; (iii) the reductive action of the 11␤-HSD1 in tissues is favored by their predominant NADPH content [19,20] and cortisone reduction only could be inhibited by the putative 7-oxo-EpiA under these conditions. These considerations lead to conclude that the 7␣-and 7␤-hydroxy-EpiA concentrations required for inhibition may never be reached and that these steroid may not be involved in the native anti-glucocorticoid paradigm [21]. Furthermore, since 7-oxoEpiA cannot be produced out of 7␣-or 7␤-hydroxy-EpiA neither by the recombinant human 11␤-HSD1 nor by human tissue fractions [7,8], we may not consider this steroid as a metabolite readily available for inhibition of the 11␤-HSD1.…”

Dehydroepiandrosterone (DHEA) and DHEA Sulfate: Roles in Brain Function and Disease

“…The 7α-hydroxylated metabolite of DHEA (7α-hydroxy-DHEA) has antiglucocorticoid effects in target tissues by competition with 11-keto glucocorticoids for access to 11β-hydroxysteroid dehydrogenase-1 [149]. Enzyme kinetic data from yeastexpressed human 11β-hydroxysteroid dehydrogenase imply that 7α-hydroxysteroid substrates are preferred to cortisone by this enzyme [150].…”

“…-induced loss of mitochondrial membrane potential by preventing Ca 2+ influx into the mitochondrial matrix [83] Inhibits NMDA-induced nitric oxide synthase activity and the production of nitric oxide in primary cultures of hippocampal neurons [84] Protect neurons from glutamate excitotoxicity, β-amyloid toxicity, and oxidative stress [49,131] Anti-inflammatory actions Inhibits IL-6 secretion from human mononuclear cells [133] Inhibits cytokine-stimulated, NF-κB-mediated transcription, partly through an antioxidant property [134] Antiglucocorticoid actions GR antagonist and can attenuate the translocation of stress-activated protein kinase-3 in rat hippocampal primary cultures [148] Suppresses the nuclear localization of the GR in response to glutamate toxicity and inhibition of GR translocation into the nucleus [131] Downregulation of the expression of glucocorticoid receptors [147] Reduces the regeneration of active glucocorticoids [149] Abbreviations: AR, androgen receptor; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; ER, estrogen receptor; GABA-A, Gammaaminobutyric acid receptor A; GR, glucocorticoid receptor; IL-6, interleukin 6; LTP, long-term potentiation; NMDA, N-methyl-D-aspartate. …”

Resolution of Colitis-Associated Inflammation

“…Due to this increase, competitive inhibition of the cellular 11-HSD1 may occur (Muller et al, 2006a) through use of the enzyme for transformation of 7-hydroxysteroid into 7-hydroxysteroids (Hennebert et al, 2007a;Muller et al, 2006b). Thus, the circulating inactive cortisone made available to the inflamed cells is not activated into cortisol which would quench the onset of immune processes.…”