Investigations of the natural occurrence of hydroxyurea in animals

我们已经发现了一种抗生素化合物，羟基脲在一种蛛形目（鲨鱼的冰鞋和鳐鱼）、小鳐鱼（Leucoraja erinacea）中含量很高，而在包括哺乳动物在内的许多其他动物中含量较低。羟基脲具有抗病毒、抗菌和抗肿瘤特性，已经或正在用于治疗各种肿瘤疾病、镰状细胞性贫血、牛皮癣、骨髓增生性疾病和艾滋病毒等传染病。它被世界卫生组织列为“基本药物”。羟基脲以前被认为不会在动物体内自然产生，所以这一发现有可能为人类医学治疗开辟新的途径。我们推测羟基脲尤其在动物的先天免疫系统中起作用。拟议的研究将确定羟基脲合成的代谢途径，以及它如何被运送到细胞内外，它在体内的周转率和降解机制。鳐将被用作这些研究的模型，因为迄今为止记录的最高水平发生在这个物种身上。羟基脲以组织特异性的方式积累，有些组织具有更高的水平。这就提出了它是在每个组织中合成还是集中转运到每个组织的问题。这些研究的一个重要方面将是确定HU如何适应一氧化氮途径，因为临床研究表明外源性应用羟基脲会增加一氧化氮水平。方法包括在示踪剂研究中使用液相色谱串联质谱法，使用15n标记的化合物在滑冰的几个组织中建立羟基脲的前体。15n -羟基脲将用于确定血浆的周转率和从各种组织中分离的膜泡中的膜转运体特性。15N-和13c -羟基脲将用于确定降解途径。两名博士生将接受这些方法的培训。这些研究将为未来研究如何利用这些知识造福人类医学提供基础。拟议研究的主要成果将是对羟基脲代谢的理解和对一氧化氮系统的更好理解，它可能在其中发挥作用。

We have discovered an antibiotic compound, hydroxyurea is found in high levels in an elasmobranch (sharks skates and rays), the little skate, Leucoraja erinacea, and lower levels in many other animals including mammals. Hydroxyurea has antiviral, antibacterial and antineoplastic properties and has been, or is, used in the treatment of a variety of neoplastic diseases, sickle cell anemia, psoriasis, myeloproliferative diseases and infectious diseases such as HIV. It is listed as an “essential medicine” by the World Health Organization. Hydroxyurea was previously not thought to occur naturally in animals so this discovery has the potential to open new avenues of treatment in human medicine. We hypothesize hydroxyurea plays a role in the innate immune system of animals especially. The proposed research will establish the metabolic pathway(s) by which hydroxyurea is synthesized as well as how it is transported into or out of cells, its rate of turnover in the body and its mechanism of degradation. The skate will be used as the model for these studies since the highest levels recorded to date occur in this species. Hydroxyurea accumulates in a tissue-specific manner with some tissues having higher levels. This raises the questions of whether it is synthesized in each tissue or centrally and is transported to each tissue. An important aspect of these studies will be to establish how HU fits into the nitric oxide pathways since clinical studies indicate exogenously applied hydroxyurea increases nitric oxide levels. The methods include using liquid chromatography tandem mass spectrometry in tracer studies using 15N-labelled compounds to establish the precursors of hydroxyurea in several tissues of the skate. 15N-hydroxyurea will be used to determine the rate of turnover in the plasma and membrane transporter characteristics in isolated membrane vesicles from various tissues of the skate. 15N- and 13C-hydroxyurea will be used to determine the degradation pathways. Two Ph.D. students will be trained in these methods. These studies will provide the basis for future studies into ways to exploit this knowledge to benefit human medicine. The main outcomes of the proposed research will be an understanding of hydroxyurea metabolism and an improved understanding of the nitric oxide system in which it likely plays a role.