Diederich S, Hanke B, Burkhardt P, Müller M, Schöneshöfer M, Bähr V, Oelkers W
Department of Endocrinology, Klinikum Benjamin Franklin, Germany.
Steroids. 1998 May-Jun;63(5-6):271-7. doi: 10.1016/s0039-128x(98)00039-7.
The presence of an 11 beta-hydroxyl group is essential for the anti-inflammatory and immunosuppressive effects of glucocorticoids. Interconversion of the 11 beta-hydroxyl into the corresponding 11 beta-keto group and vice versa by 11 beta-hydroxysteroid-dehydrogenase (11 beta-HSD) may thus play a pivotal role in the efficacy of these steroids. Therefore, we have compared the metabolism of the endogenous glucocorticoid cortisol (F) with that of synthetic 9 alpha-fluorinated steroids by 11 beta-HSDs in humans in vivo and in vitro. Whereas 30% of the free steroids in urine after oral administration of 5 mg of F is F itself and 70% the inactive keto-product cortisone (E), the urinary excretion of an identical dose of oral 9 alpha-fluorocortisol (9 alpha FF) is 90% 9 alpha FF and 10% inactive 9 alpha-fluorocortisone (9 alpha FE). Kidney slices similarly convert F much faster to E than 9 alpha FF to 9 alpha FE; conversely, renal 11 beta-reduction of 9 alpha FE to 9 alpha FF is much more effective than that of E to F. Kinetic analyses in human kidney cortex microsomes prove that the preference of fluorinated steroids for reduction in human kidney slices is catalyzed by 11 beta-HSD type II: the NADH-dependent conversion of 11-dehydro-dexamethasone (DH-D), another fluorinated steroid, to dexamethasone (D) is very effective (high affinity, high Vmax), whereas reduction of E to F is very slow. In human liver microsomes (11 beta-HSD type I), nonfluorinated (E) and fluorinated 11-dehydrosteroids (DH-D) are both reduced to their corresponding active 11-hydroxyderivatives but with a Michaelis-Menten constant about 20-fold higher than for kidney microsomes (11 beta-HSD-II). Our results suggest that the decreased renal 11 beta-oxidation of 9 alpha-fluorinated steroids may offer pharmacokinetic advantages for renal immunosuppression. Furthermore, administration of fluorinated 11-dehydrosteroids is a new and exciting idea in glucocorticoid therapy in that small amounts of oral DH-D may pass the liver largely unmetabolized (11 beta-HSD-I has low affinity for such steroids) and may then be activated to D by high-affinity 11 beta-HSD-II, thus allowing selective immunosuppression in organs expressing 11 beta-HSD-II (kidney and colon).
11β-羟基的存在对于糖皮质激素的抗炎和免疫抑制作用至关重要。11β-羟基类固醇脱氢酶（11β-HSD）将11β-羟基与相应的11β-酮基相互转化，反之亦然，因此可能在这些类固醇的疗效中起关键作用。因此，我们在体内和体外比较了人体内11β-HSD对内源性糖皮质激素皮质醇（F）与合成的9α-氟化类固醇的代谢情况。口服5mg F后，尿液中30%的游离类固醇是F本身，70%是无活性的酮产物可的松（E），而相同剂量的口服9α-氟皮质醇（9αFF）的尿排泄量为90%的9αFF和10%无活性的9α-氟可的松（9αFE）。肾切片同样将F转化为E的速度比将9αFF转化为9αFE的速度快得多；相反，肾脏将9αFE还原为9αFF的11β-还原作用比将E还原为F的作用更有效。人肾皮质微粒体的动力学分析证明，氟化类固醇在人肾切片中还原的偏好是由II型11β-HSD催化的：另一种氟化类固醇11-脱氢地塞米松（DH-D）依赖NADH转化为地塞米松（D）非常有效（高亲和力，高Vmax），而将E还原为F则非常缓慢。在人肝微粒体（I型11β-HSD）中，非氟化（E）和氟化的11-脱氢类固醇（DH-D）都被还原为相应的活性11-羟基衍生物，但米氏常数比肾微粒体（II型11β-HSD）高约20倍。我们的结果表明，9α-氟化类固醇肾11β-氧化的降低可能为肾免疫抑制提供药代动力学优势。此外，给予氟化的11-脱氢类固醇在糖皮质激素治疗中是一个新的令人兴奋的想法，因为少量口服DH-D可能在很大程度上未经代谢通过肝脏（I型11β-HSD对这类类固醇亲和力低），然后可能被高亲和力的II型11β-HSD激活为D，从而允许在表达II型11β-HSD的器官（肾脏和结肠）中进行选择性免疫抑制。
