Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
Chem Biol Interact. 2011 May 30;191(1-3):234-8. doi: 10.1016/j.cbi.2011.01.019. Epub 2011 Jan 27.
Inhaled corticosteroids (ICS) are a mainstay anti-inflammatory therapy for the management of asthma. ICS are synthetic glucocorticoids that are structurally similar to the natural active human glucocorticoid cortisol. Steroid transforming enzymes of the aldo-keto reductase (AKR) family, namely AKR1D1 (5β-steroid reductase) and AKR1C1-4 (ketosteroid reductases) are implicated in the systemic metabolism of cortisol in liver. In this study, the activities of these AKR1 enzymes on cortisol and two ICS compounds budesonide (BUD) and flunisolide (FLU) were investigated. It was found that the catalytic efficiency of AKR1D1 for the reduction of the double bond in cortisol was 4- and 10-fold higher than the catalytic efficiencies of AKR1D1 with FLU and BUD, respectively. This suggests that compared to cortisol, for which the 5β-reduction is a major metabolic pathway, a lower degree of systemic (hepatic) metabolism of BUD and FLU via AKR1D1 takes place. In addition, BUD potently inhibited AKR1D1 and AKR1C4, the key steroid metabolizing enzymes in liver, which may disrupt endogenous steroid hormone metabolism and thus contribute to BUD-induced systemic effects. Activities of AKR1C1-3 on cortisol and the two ICS compounds (targeting the 20-keto group) suggest these enzymes may be involved in the local (lung) metabolism of these glucocorticoids.
吸入性皮质类固醇（ICS）是治疗哮喘的主要抗炎治疗方法。ICS 是合成的糖皮质激素，其结构与天然活性人类糖皮质激素皮质醇相似。醛酮还原酶（AKR）家族的类固醇转化酶，即 AKR1D1（5β-类固醇还原酶）和 AKR1C1-4（酮固醇还原酶），参与皮质醇在肝脏中的全身代谢。在这项研究中，研究了这些 AKR1 酶对皮质醇和两种 ICS 化合物布地奈德（BUD）和氟替卡松（FLU）的作用。结果发现，AKR1D1 对皮质醇双键的还原催化效率分别比 FLU 和 BUD 的催化效率高 4 倍和 10 倍。这表明，与 5β-还原是主要代谢途径的皮质醇相比，通过 AKR1D1 发生的 BUD 和 FLU 的全身（肝脏）代谢程度较低。此外，BUD 强烈抑制 AKR1D1 和 AKR1C4，这是肝脏中关键的类固醇代谢酶，这可能会破坏内源性类固醇激素代谢，从而导致 BUD 引起的全身效应。AKR1C1-3 对皮质醇和两种 ICS 化合物（靶向 20-酮基）的活性表明，这些酶可能参与这些糖皮质激素的局部（肺部）代谢。
