Inter-conversion of 7α- and 7β-hydroxy-dehydroepiandrosterone by the human 11β-hydroxysteroid dehydrogenase type 1

The dehydroepiandrosterone (DHEA) 7α-hydroxylation in humans takes place in the liver, skin, and brain. These organs are targets for the glucocorticoid hormones where 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates cortisone through its reduction into cortisol. The putative interference of 7α-hydroxy-DHEA with the 11β-HSD1-catalyzed reduction of cortisone into cortisol has been confirmed in preliminary works with human liver tissue preparations of the enzyme demonstrating the transformation of 7α-hydroxy-DHEA into 7-oxo-DHEA and 7β-hydroxy-DHEA. However, the large production of 7β-hydroxy-DHEA could not be explained satisfactorily. Therefore our objective was to study the role in the metabolism of oxygenated DHEA by recombinant human 11β-HSD1 expressed in yeast. The 7α- and 7β-hydroxy-DHEA were each oxidized into 7-oxo-DHEA with quite dissimilar KM (70 and 9.5 μM, respectively) but at equivalent Vmax. In contrast, the 11β-HSD1-mediated reduction of 7-oxo-DHEA led to the production of both 7α- and 7β-hydroxy-DHEA with equivalent KM (1.1 μM) but with a 7β-hydroxy-DHEA production characterized by a significantly greater Vmax. The 7α-hydroxy-DHEA produced by the cytochrome CYP7B1 in tissues may exert anti-glucocorticoid effects through interference with the 11β-HSD1-mediated cortisone reduction.