Discovery of Natural Steroid 5 Alpha-Reductase Inhibitors.
Discovery of Natural Steroid 5 Alpha-Reductase Inhibitors.
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DOI：
10.1089/adt.2018.870
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发表时间：
2019-02-01
影响因子：
1.8
通讯作者：
Ingkaninan, Kornkanok
中科院分区：
文献类型：
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作者：
Srivilai, Jukkarin;Minale, Genet;Ingkaninan, Kornkanok
人类类固醇5α-还原酶(S5AlphaRs)和NADPH不可逆转地将睾酮还原为更有效的双氢睾酮(DHT)。S5AlphaR抑制剂是治疗DHT依赖型疾病的有效药物，包括良性前列腺增生症、雄激素性脱发和毛发生长以及痤疮。有三种S5alphaR同工酶，需要比目前批准的非那雄胺和度他雄胺更安全和更具同工酶选择性的抑制剂。在这项研究中，我们回顾了用于筛选S5alphaR抑制活性的方法，并描述了表征草药制剂及其成分抑制S5alphaRs的能力的研究。我们发现在IC50年代对用作标准的非那雄胺和度他雄胺的研究之间存在巨大差异。因此，我们提出了几点建议：稳定的同工酶特异性转导系统需要创建标准化的酶/微体制剂，并且应该测试所有三种同工酶以及雄激素受体的结合；商定的反应条件，特别是底物浓度，以及优化的高通量筛选的分离/定量方法；系统地筛选草药化合物，并最广泛地使用Leads来开发更有效的同工酶特异性抑制剂。
Human steroid 5 alpha-reductases (S5alphaRs) and NADPH irreversibly reduce testosterone to the more potent dihydrotestosterone (DHT). S5alphaR inhibitors are useful treatments for DHT-dependent diseases, including benign prostatic hyperplasia, androgenic alopecia and hair growth, and acne. There are three S5alphaR isozymes, and there is a need for safer and more isozyme selective inhibitors than finasteride and dutasteride currently licensed. In this study, we review the methods used to screen for S5alphaR inhibitory activity and describe studies that characterize the ability of herbal preparations and their constituents to inhibit S5alphaRs. We identified enormous variations between studies in IC50s for finasteride and dutasteride used as standards. Accordingly, we make several recommendations: Stable isozyme specific transfection systems need creating a standardized enzyme/microsome preparation and all three isozymes, as well as androgen receptor binding, should be tested; agreed reaction conditions, especially the substrate concentrations, and separation/quantitation method optimized for high throughput screening; systematic screening of herbal compounds and most extensive use of leads to develop more potent and isozyme specific inhibitors.