Investigations of the natural occurrence of hydroxyurea in animals

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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.