Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3
Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3
复制标题
DOI：
10.1016/j.cbi.2010.12.012
复制
发表时间：
2011-05-30
影响因子：
5.1
通讯作者：
Rizner, T. Lanisnik
中科院分区：
文献类型：
--
作者：
Beranic, N.;Gobec, S.;Rizner, T. Lanisnik
人醛酮还原酶1C 1和1C 3（AKR 1C 1和AKR 1C 3）是孕酮作用的前受体调节中重要的20-酮类固醇还原酶。AKR 1C 1和AKR 1C 3都将孕酮转化为效力较低的代谢物20 α-羟孕酮，尽管AKR 1C 1比AKR 1C 3具有更高的催化效率。最近，我们报道了AKR 1C 1和AKR 1C 3在卵巢子宫内膜异位症（一种复杂的雌激素依赖性疾病）中的显著上调。子宫内膜异位症的典型特征是刺激子宫内膜组织增生的雌二醇的形成增加，以及保护性孕酮的作用受到干扰。虽然孕激素已被用于治疗子宫内膜异位症自20世纪60年代以来。它们的详细作用机制仍不完全清楚。在本研究中，我们评估了孕激素对前受体调节酶AKR 1C 1和AKR 1C 3的潜在抑制作用。我们研究了以下孕激素作为重组AKR 1C 1和AKR 1C 3催化的孕酮还原的抑制剂：孕酮衍生物（地屈孕酮，其代谢物，20 α-羟基地屈孕酮和醋酸甲羟孕酮），19-去甲睾酮衍生物（去氧孕烯，炔诺酮和左炔诺孕酮），和雄激素达那唑。地屈孕酮、醋酸甲羟孕酮、20 α-羟基地屈孕酮和炔诺酮抑制AKR 1C 1和AKR 1C 3，K（i）值分别为1.9 μ M、7.9 μ M、20.8 μ M和48.0 μ M，以及0.5 μ M、1.4 μ M、18.2 μ M和6.6 μ M。左炔诺孕酮和去氧孕烯优先抑制AKR 1C 3，K（i）值分别为5.6 μ M和39.1 μ M。因此，我们的数据表明，dydrogastrin，醋酸甲羟孕酮，20 α-羟基dydrogastrin和norethinodrone抑制AKR 1C 1和AKR 1C 3在体外，虽然他们的生理抑制作用仍需要进一步评估。此外，我们研究了是否可以通过AKR 1C 1和AKR 1C 3将dydrogestin代谢为其活性20 α-羟基代谢物。AKR 1C 1以高催化效率转化dydrogastrin，而AKR 1C 3活性较低，这表明体内dydrogastrin主要由AKR 1C 1代谢。Dydrogastrin与AKR 1C 1和AKR 1C 3的对接模拟也支持这些实验数据。(C)2010爱思唯尔爱尔兰有限公司版权所有。
The human aldo-keto reductases 1C1 and 1C3 (AKR1C1 and AKR1C3) are important 20-ketosteroid reductases in pre-receptor regulation of progesterone action. Both AKR1C1 and AKR1C3 convert progesterone to the less potent metabolite 20 alpha-hydroxyprogesterone, although AKR1C1 has a higher catalytic efficiency than AKR1C3. Recently, we reported significant up-regulation of AKR1C1 and AKR1C3 in ovarian endometriosis, a complex estrogen-dependent disease. The typical characteristics of endometriosis are increased formation of estradiol, which stimulates proliferation of endometriotic tissue, and disturbed action of the protective progesterone. Although progestins have been used for treatment of endometriosis since the 1960s. their detailed mechanisms of action are still not completely understood. In the present study, we evaluated the potential inhibitory effects of progestins on the pre-receptor regulatory enzymes AKR1C1 and AKR1C3. We examined the following progestins as inhibitors of progesterone reduction catalyzed by recombinant AKR1C1 and AKR1C3: progesterone derivatives (dydrogesterone, its metabolite, 20 alpha-hydroxydydrogesterone and medroxyprogesterone acetate), 19-nortestosterone derivatives (desogestrel, norethinodrone and levonorgestrel), and the androgen danazol. Dydrogesterone, medroxyprogesterone acetate, 20 alpha-hydroxydydrogesterone and norethinodrone inhibited AKR1C1 and AKR1C3 with K(i) values of 1.9 mu M, 7.9 mu M, 20.8 mu M and 48.0 mu M, and of 0.5 mu M, 1.4 mu M, 18.2 mu M and 6.6 mu M, respectively. Levonorgestrel and desogestrel preferentially inhibited AKR1C3 with K(i) values of 5.6 mu M and 39.1 mu M, respectively. Our data thus show that dydrogesterone, medroxyprogesterone acetate, 20 alpha-hydroxydydrogesterone and norethinodrone inhibit AKR1C1 and AKR1C3 in vitro, although their physiological inhibitory effects still need to be evaluated further. Additionally, we investigated whether progestin dydrogesterone can be metabolized to its active 20 alpha-hydroxymetabolite by AKR1C1 and AKR1C3. AKR1C1 converted dydrogesterone with a high catalytic efficiency while AKR1C3 was less active, which suggests that in vivo dydrogesterone is metabolized mainly by AKR1C1. Docking simulations of dydrogesterone into AKR1C1 and AKR1C3 also support these experimental data. (C) 2010 Elsevier Ireland Ltd. All rights reserved.