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、某些癌症和其他与(性)分化、生长和发育有关的毒性。多种化合物已被确定为类固醇合成的抑制剂，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。芳香酶(CYP19)和类固醇5α-还原酶(SRD5A)是类固醇合成的关键酶，它们分别产生最强的雌激素和雄激素17？雌二醇和DHT，参与多种内分泌病理过程。我们假设，具有类似内源性雄激素结构的天然或合成化合物(雄烯二酮、睾酮)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。我研究计划的目标是：1)确定天然或合成化学品的结构要求，使其能够干扰CYP19和SRD5A的催化活性或基因表达，以及AR信号转导；2)通过细胞检测，阐明酶抑制/诱导或AR抗菌素(激动剂)的体外机制(涉及的信号通路)；3)在生物发光小鼠模型中，评估这些化合物的体内生物活性。应用纳米技术，在体外具有强大的和可能有益的作用，但在体内效果不佳的化合物将被包裹在纳米颗粒中，其性质将改善体内给药和生物功效。这项研究计划将提供一个更好的理解机制(信号通路)涉及的细胞色素P19，SRD5A和AR的调节。它将确定新的结构，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。它将评估或改善体外活性化合物的体内有效性，为将体外效应外推到体内情况提供重要信息。

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.