摘要
胆固醇-5,6-环氧化物水解酶(ChEH)是存在于哺乳动物中的一种由两种胆固醇基因相关酶组成的异寡聚复合体,能调控哺乳动物的 生长发育过程。据推测,这个复合体被识别后,激活了一条以5,6-环氧酶(5,6-EC)为中心的新的代谢途径。接下来会合成一些5,6 -EC的共轭产物,以及已知会和ChEH产生相互作用的生物胺。根据它们的结构,这些甾类生物碱在低剂量时体现出能诱导细胞分化的 特性,这表明它们可能作为代谢产物而存在。这些化合物中有一个被命名为Dendrogenin A(DDA),是最近在哺乳动物组织中发现 的。研究表明DDA是由5,6α-环氧胆固醇和组胺立体选择性结合生成的,此过程由一种尚不明确的酶催化。DDA可以在多个器官的正 常组织中检测到,但癌细胞除外,而且在乳腺肿瘤患者体内它的水平也降低,这些证明癌变过程中存在DDA代谢的失调。DDA也能够 控制植入小鼠的肿瘤细胞的生长,提高动物的存活率。此外,DDA还能在耳聋临床前模型中有效地使听力得到恢复。DDA的这些性质 ,包括能抑制肿瘤,说明它有维持细胞完整,促进细胞分化的生理作用。DDA是迄今为止有记录的在哺乳动物中发现的第一个甾体类 生物碱。它的发现揭示了在哺乳动物体内胆固醇和组胺代谢交叉处的一条新的代谢途径,这条途径的代谢产物能够起到肿瘤抑制和神经保护剂的作用。
关键词: 制动体系,癌症,胆固醇,胆固醇-5
Current Medicinal Chemistry
Title:Dendrogenin A: A Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties
Volume: 22 Issue: 30
Author(s): Florence Dalenc, Marc Poirot and Sandrine Silvente-Poirot
Affiliation:
关键词: 制动体系,癌症,胆固醇,胆固醇-5
摘要: Cholesterol-5,6-epoxide hydrolase (ChEH) in mammals is a heterooligomeric complex of two cholesterogenic enzymes that control mammalian developmental programs. Following the identification of this complex, it was hypothesized that a new metabolic pathway existed that centered on 5,6-epoxy cholesterols (5,6-EC). Conjugation products of 5,6-EC with biogenic amines known to interact with ChEH subunits were synthesized. According to their structures, these steroidal alkaloids showed the specific potency to induce cell differentiation at low doses, suggesting their possible existence as metabolites. One of these compounds, named dendrogenin A (DDA), was recently discovered in mammalian tissues. It was shown that DDA arises from the stereoselective enzymatic conjugation of 5,6α-epoxy-cholesterol with histamine by an as-yet-unidentified enzyme. DDA was detected in normal tissues from several organs but not in cancer cells and its level was decreased in breast tumors from patients, evidencing a deregulation of DDA metabolism during carcinogenesis. DDA was also able to control the growth of tumor cells implanted in mice and improve animal survival. In addition, DDA efficiently restored hearing in a preclinical model of deafness. These biological properties of DDA, as well as its decreased levels in tumors, suggest a physiological function in maintaining cell integrity and differentiation. DDA is the first steroidal alkaloid found to date in mammals. Its discovery reveals the existence of a new metabolic pathway in mammals at the crossroads of cholesterol and histamine metabolism that leads to the production of a metabolic tumor suppressor and neuroprotective agent.
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Florence Dalenc, Marc Poirot and Sandrine Silvente-Poirot , Dendrogenin A: A Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties, Current Medicinal Chemistry 2015; 22 (30) . https://dx.doi.org/10.2174/0929867322666150716114912
DOI https://dx.doi.org/10.2174/0929867322666150716114912 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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