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Oxoreductase and Dehydrogenase Activities of the Human and Rat 11ß-Hydroxysteroid Dehydrogenase Type 2 Enzyme¹

Laboratory of Molecular Hypertension, Baker Institute of Medical Research, Prahran, Victoria 3181, Australia

Address all correspondence and requests for reprints to: Paolo Ferrari, M.D., Laboratory of Molecular Hypertension, Baker Institute of Medical Research, Prahran, Victoria 3181, Australia.

The 11ß-hydroxysteroid dehydrogenase type 2 enzyme (11ßHSD2) metabolizes glucocorticoids into their inactive 11-keto metabolites. Although the type 1 enzyme (11ßHSD1) displays both oxidative and reductive activity, to date 11ßHSD2 has been shown to have dehydrogenase activity only.

In this study we compared both dehydrogenase and reductase characteristics of the cloned rat 11ßHSD1 and rat and human 11ßHSD2 for three different 11-hydroxysteroid substrates, cortisol (F), corticosterone (B), and dexamethasone (Dex), and the corresponding 11-keto metabolites, cortisone (E), 11-dehydrocorticosterone (A), and 11-dehydrodexamethasone (DH-Dex), respectively.

In cell homogenates expressing either the rat or the human 11ßHSD2, the relative potency for the dehydrogenase reaction was B > F > Dex. Although there was no reduction of A or E, DH-Dex was readily converted to Dex 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 11ßHSD1, the equilibrium was on the reductase side for all substrates. Dehydrogenation of B or F was more potent with rat 11ßHSD2 than with rat 11ßHSD1. There was no detectable 11ßHSD1 oxidation of Dex.

These data indicate that both the cloned human and rat 11ßHSD2 reduce DH-Dex and do this more readily than they oxidize Dex. Thus, 11ßHSD2 seems also to be a bidirectional enzyme, although no reduction of the physiological compounds A and E was observed.

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