Investigations of the natural occurrence of hydroxyurea in animals

我们已经发现了一种抗生素化合物，羟基脲在一种软脊椎动物(鲨鱼、溜冰鞋和银鱼)、小溜冰鞋和银合欢中含量很高，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、抗细菌和抗肿瘤特性，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”。羟基脲此前被认为不会在动物体内自然产生，因此这一发现有可能为人类医学开辟新的治疗途径。我们推测羟基脲在动物的先天免疫系统中起着特别重要的作用。这项拟议的研究将建立合成羟基脲的代谢途径(S)，以及羟基脲是如何运输进或运出细胞的，它在体内的周转速度及其降解机制。溜冰鞋将被用作这些研究的模型，因为迄今为止记录到的最高水平出现在这种物种中。羟基尿素以组织特有的方式积聚，某些组织的含量较高。这就提出了一个问题，即它是在每个组织中合成的，还是集中合成并运输到每个组织中的。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，外源性应用羟基尿素会增加一氧化氮水平。这些方法包括在示踪剂研究中使用15N标记的化合物来建立溜冰鞋几个组织中羟基尿素的前体。15N-羟基尿素将被用来测定冰鞋不同组织中的血浆周转率和离体膜囊泡的膜转运蛋白特性。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一知识造福人类医学提供基础。这项拟议研究的主要成果将是对羟基尿素代谢的理解，以及对它可能在其中发挥作用的一氧化氮系统的更好理解。

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.