Li K X, Obeyesekere V R, Krozowski Z S, Ferrari P
Laboratory of Molecular Hypertension, Baker Institute of Medical 1esearch, Prahran, Victoria, Australia.
Endocrinology. 1997 Jul;138(7):2948-52. doi: 10.1210/endo.138.7.5232.
The 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11betaHSD2) metabolizes glucocorticoids into their inactive 11-keto metabolites. Although the type 1 enzyme (11betaHSD1) displays both oxidative and reductive activity, to date 11betaHSD2 has been shown to have dehydrogenase activity only. In this study we compared both dehydrogenase and reductase characteristics of the cloned rat 11betaHSD1 and rat and human 11betaHSD2 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 11betaHSD2, 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 11betaHSD1, the equilibrium was on the reductase side for all substrates. Dehydrogenation of B or F was more potent with rat 11betaHSD2 than with rat 11betaHSD1. There was no detectable 11betaHSD1 oxidation of Dex. These data indicate that both the cloned human and rat 11betaHSD2 reduce DH-Dex and do this more readily than they oxidize Dex. Thus, 11betaHSD2 seems also to be a bidirectional enzyme, although no reduction of the physiological compounds A and E was observed.
2型11β-羟基类固醇脱氢酶（11βHSD2）可将糖皮质激素代谢为无活性的11-酮代谢产物。虽然1型酶（11βHSD1）兼具氧化和还原活性，但迄今为止，11βHSD2仅表现出脱氢酶活性。在本研究中，我们比较了克隆的大鼠11βHSD1以及大鼠和人类11βHSD2对三种不同的11-羟基类固醇底物（皮质醇（F）、皮质酮（B）和地塞米松（Dex））以及相应的11-酮代谢产物（可的松（E）、11-脱氢皮质酮（A）和11-脱氢地塞米松（DH-Dex））的脱氢酶和还原酶特性。在表达大鼠或人类11βHSD2的细胞匀浆中，脱氢酶反应的相对效力为B＞F＞Dex。虽然未观察到A或E的还原，但DH-Dex很容易转化为Dex，且平衡状态远偏向11-羟基代谢产物一侧。匀浆中DH-Dex的还原受到甘草次酸和甘珀酸的抑制，其半数抑制浓度分别为80 nM和100 nM。在转染了大鼠11βHSD1的完整细胞中，所有底物的平衡均偏向还原酶一侧。大鼠11βHSD2对B或F的脱氢作用比大鼠11βHSD1更强。未检测到Dex的11βHSD1氧化作用。这些数据表明，克隆的人类和大鼠11βHSD2均可还原DH-Dex，且还原作用比氧化Dex更易发生。因此，11βHSD2似乎也是一种双向酶，尽管未观察到生理化合物A和E的还原。
