Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave PSC 527 Los Angeles, CA 90089, USA.
Curr Pharm Des. 2011;17(2):151-67. doi: 10.2174/138161211795049589.
The enzyme steroid 5α reductase (S5α R) catalyzes the conversion of Δ⁴-3-ketosteroid precursors--such as testosterone, progesterone and androstenedione--into their 5α-reduced metabolites. Although the current nomenclature assigns five enzymes to the S5α R family, only the types 1 and 2 appear to play an important role in steroidogenesis, mediating an overlapping set of reactions, albeit with distinct chemical characteristics and anatomical distribution. The discovery that the 5α-reduced metabolite of testosterone, 5α-dihydrotestosterone (DHT), is the most potent androgen and stimulates prostatic growth led to the development of S5α R inhibitors with high efficacy and tolerability. Two of these agents, finasteride and dutasteride, have received official approval for the treatment of benign prostatic hyperplasia and are being tested for prevention of prostate cancer. Finasteride is also approved for male-pattern alopecia and has been shown to induce very limited side effects. Over the last decade, converging lines of evidence have highlighted the role of 5α-reduced steroids and their precursors in brain neurotransmission and behavioral regulation. Capitalizing on these premises, we and other groups have recently investigated the role of S5α R in neuropsychiatric disorders. Our preliminary data suggest that S5 R inhibitors may elicit therapeutic effects in a number of disorders associated to dopaminergic hyperreactivity, including psychotic disorders, Tourette syndrome and impulse control disorders. In the present article, we review emerging preclinical and clinical evidence related to these effects, and discuss some of the potential mechanisms underlying the role of S5α R in the pathophysiology of mental disorders.
酶甾体 5α 还原酶（S5α R）催化 Δ⁴-3-酮甾体前体（如睾酮、孕酮和雄烯二酮）转化为它们的 5α-还原代谢物。尽管当前的命名法将五种酶分配给 S5α R 家族，但只有 1 型和 2 型似乎在类固醇生成中发挥重要作用，介导重叠的反应集，尽管具有不同的化学特征和解剖分布。发现睾酮的 5α-还原代谢物 5α-二氢睾酮（DHT）是最强的雄激素，并刺激前列腺生长，这导致了具有高效和耐受性的 S5α R 抑制剂的开发。其中两种药物，非那雄胺和度他雄胺，已获得治疗良性前列腺增生的官方批准，并正在测试用于预防前列腺癌。非那雄胺也被批准用于男性型脱发，并已被证明会引起非常有限的副作用。在过去的十年中，越来越多的证据强调了 5α-还原类固醇及其前体在脑神经传递和行为调节中的作用。利用这些前提，我们和其他小组最近研究了 S5α R 在神经精神疾病中的作用。我们的初步数据表明，S5α R 抑制剂可能在许多与多巴胺能过度反应相关的疾病中产生治疗效果，包括精神病、图雷特综合征和冲动控制障碍。在本文中，我们综述了与这些作用相关的新兴临床前和临床证据，并讨论了 S5α R 在精神障碍病理生理学中作用的一些潜在机制。
