Interactions of natural and synthetic compounds with steroidogenic enzymes and sex hormone receptor signalling

社会越来越关注可能扰乱内分泌过程的化学品，这些化学品可能导致生殖问题、某些癌症和与（性）分化、生长和发育有关的其他毒性。各种化合物已被确定为类固醇生成的抑制剂，包括杀虫剂、药物和天然化合物。这些研究大多是体外研究，很少有体内研究。芳香化酶（CYP19）和类固醇5 α -还原酶（SRD5A）是特别有趣的，因为它们是产生最有效的雌激素和雄激素17ß-雌二醇和DHT的关键甾体原酶，并参与各种内分泌病理。我们假设具有类似内源性雄激素（雄烯二酮，睾酮）结构的天然或合成化合物作为CYP19和SRD5A活性的抑制剂（利用雄激素作为天然底物）和雄激素受体（AR）的拮抗剂。我的研究计划的目标是：1)确定天然或合成化学物质的结构要求，使它们能够干扰CYP19和SRD5A的催化活性或基因表达，以及AR信号；2)在体外细胞实验中阐明酶抑制/诱导或AR（激动作用）的机制（涉及的信号通路）；3)在生物发光小鼠模型中评价这些化合物的生物活性。应用纳米技术，在体外具有有效和可能有益作用，但在体内效果不佳的化合物将被封装在纳米颗粒中，其特性将改善体内递送和生物功效。该研究计划将更好地理解CYP19、SRD5A和AR调控的机制（信号通路）。它将发现新的结构，可能导致开发新的CYP19和SRD5A抑制剂或AR拮抗剂，可用于治疗各种疾病。它将评估或提高在体外显示有活性的化合物在体内的有效性，提供关于在哪些条件下有效地推断体外作用到体内情况的重要信息。

There is increasing societal concern regarding chemicals that may disrupt endocrine processes, potentially resulting in reproductive problems, certain cancers and other toxicities related to (sexual) differentiation, growth and development. Various compounds have been identified as inhibitors of steroidogenesis, including pesticides, drugs and natural compounds. Most of these are in vitro studies, few in vivo studies exist. Aromatase (CYP19) and steroid 5alpha-reductase (SRD5A) are of particular interest as they are the key steroidogenic enzymes producing the most potent estrogens and androgens, 17ß-estradiol and DHT, respectively, and are involved in various endocrine pathologies. We hypothesize that natural or synthetic compounds with structures resembling the endogenous androgens (androstenedione, testosterone) act as inhibitors of CYP19 and SRD5A activity (which utilize androgens as natural substrates) and as antagonists of the androgen receptor (AR). The objectives of my research programme are to 1) identify the structural requirements of natural or synthetic chemicals enabling them to interfere with the catalytic activity or gene expression of the CYP19 and SRD5A, as well as with AR signalling; 2) elucidate mechanisms (signalling pathways involved) of enzyme inhibition/induction or AR ant(agonism) in vitro in cell-based assays; 3) evaluate the biological activity of these compounds in vivo in bioluminescent mouse models. Applying nanotechnology, compounds with potent and possibly beneficial effects in vitro, but poorly effective in vivo, will be encapsulated in nanoparticles with properties that will improve in vivo delivery and biological efficacy. This research programme will provide a better understanding of the mechanisms (signalling pathways) involved in CYP19, SRD5A and AR regulation. It will identify novel structures that may lead to the development of novel CYP19 and SRD5A inhibitors or AR antagonist which could be used to treat various diseases. It will evaluate or improve the effectiveness in vivo of compounds shown to be active in vitro providing important information on the conditions under which it is valid to extrapolate in vitro effects to an in vivo situation.