Widespread Natural Occurrence of Hydroxyurea in Animals.

David I Fraser,Andrew Sevier,Jacob W Robinson,Kyle T Liu,James S Ballantyne,Pierre H R Ouellette,Michelle Pyle,Bryan J Reid,Emily Hawkins,Markus Michael Bachschmid

doi:10.1371/journal.pone.0142890

Abstract

Here we report the widespread natural occurrence of a known antibiotic and antineoplastic compound, hydroxyurea in animals from many taxonomic groups.Hydroxyurea occurs in all the organisms we have examined including invertebrates (molluscs and crustaceans), fishes from several major groups, amphibians and mammals. The species with highest concentrations was an elasmobranch (sharks, skates and rays), the little skate Leucoraja erinacea with levels up to 250 μM, high enough to have antiviral, antimicrobial and antineoplastic effects based on in vitro studies. Embryos of L. erinacea showed increasing levels of hydroxyurea with development, indicating the capacity for hydroxyurea synthesis. Certain tissues of other organisms (e.g. skin of the frog (64 μM), intestine of lobster (138 μM) gills of the surf clam (100 μM)) had levels high enough to have antiviral effects based on in vitro studies. Hydroxyurea is widely used clinically in the treatment of certain human cancers, sickle cell anemia, psoriasis, myeloproliferative diseases, and has been investigated as a potential treatment of HIV infection and its presence at high levels in tissues of elasmobranchs and other organisms suggests a novel mechanism for fighting disease that may explain the disease resistance of some groups. In light of the known production of nitric oxide from exogenously applied hydroxyurea, endogenous hydoxyurea may play a hitherto unknown role in nitric oxide dynamics.

Highlights

Hydroxyurea is a remarkable compound that has been known to science since1869 when it was first synthesized [1]
The nominal concentrations we report for the little skate are in the range of concentrations causing 50% inhibition (ED50) of a variety of processes including DNA synthesis, ribonucleotide reductase activity in viruses and growth of some cell types (Table 1)
The values we report for L. erinacea are in the range that would affect some viral and bacterial processes (Fig 2a and Table 1)

Summary

Introduction

Hydroxyurea is a remarkable compound that has been known to science since1869 when it was first synthesized [1]. Various studies show it has antiviral, antibacterial, and antineoplastic properties [2]. Its mechanism of action involves inhibition of ribonucleotide reductase (EC 1.17.4.1) which inhibits DNA synthesis [3] in a variety of organisms. It is, or has been used in the treatment of a variety of neoplastic diseases, sickle cell anemia, psoriasis, myeloproliferative diseases and infectious diseases such as HIV [2]. We examined the levels of hydroxyurea in tissues of representative of invertebrate and vertebrate groups

Materials and Methods

Results and Discussion

Conclusions