Oxoreductase and dehydrogenase activities of the human and rat 11 beta-hydroxysteroid dehydrogenase type 2 enzyme

The 11 beta-hydroxysteroid dehydrogenase type 2 enzyme (11 beta HSD2) metabolizes glucocorticoids into their inactive Il-keto metabolites. Although the type 1 enzyme (11 beta HSD1) displays both oxidative and reductive activity, to date 11 beta HSD2 has been shown to have dehydrogenase activity only. In this study we compared both dehydrogenase and reductase characteristics of the cloned rat 11 beta HSD1 and rat and human 11 beta HSD2 for three different 11-hydroxysteroid substrates, cortisol (F), corticosterone (B), and dexamethasone (Dex), and the corresponding Il-keto metabolites, cortisone (E), 11-dehydrocorticosterone (A), and 11-dehydrodexamethasone (DH-Dex), respectively. In cell homogenates expressing either the rat or the human 11 beta HSD2, the relative potency for the dehydrogenase reaction was B > F > Dex. Although there was no reduction of A or E, DH-Des was readily converted to Des with an equilibrium far on the side of the 11-hydroxy metabolite. DH-Dex reduction in homogenates was inhibited by both glycyrrhetinic acid and carbenoxolone, with a 50% inhibition at 80 and 100 nM, respectively. In intact cells transfected with rat 11 beta HSD1, the equilibrium was on the reductase side for all substrates. Dehydrogenation of B or F was more potent with rat 11 beta HSD2 than with rat 11 beta HSD1. There was no detectable 11 beta HSD1 oxidation of Dex. These data indicate that both the cloned human and rat 1I beta HSD2 reduce DH-Dex and do this more readily than they oxidize Dex. Thus, 11 beta HSD2 seems also to be a bidirectional enzyme, although no reduction of the physiological compounds A and E was observed.