The native anti-glucocorticoid paradigm

Circulating 3β-hydroxysteroids including dehydroepiandrosterone (DHEA) are 7α-hydroxylated by the cytochrome P450-7B1 in the liver, skin and brain, which are the target organs of glucocorticoids. Anti-glucocorticoid effects with 7α-hydroxy-DHEA were observed in vivo without an interference with glucocorticoid binding to its receptor. In the organs mentioned above, the circulating inactive cortisone was reduced into active cortisol by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). We demonstrated that 7α-hydroxy-DHEA was also a substrate for this enzyme. Studies of the 11β-HSD1 action on 7α-hydroxy-DHEA showed the reversible production of 7β-hydroxy-DHEA through an intermediary 7-oxo-DHEA, and the kinetic parameters favored this production over that of active glucocorticoids. Both the production of 7α-hydroxysteroids and their interference with the activation of cortisone into cortisol are basic to the concept of native anti-glucocorticoids efficient at their production site. This opens a promising new area for research.