Widespread Natural Occurrence of Hydroxyurea in Animals

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.

Genome-wide insights on gastrointestinal nematode resistance in autochthonous Tunisian sheep

“…We observed two organic cation transporters, SLC22A4 (OCTN1) and SLC22A5 (OCTN2) which are carriers of hydroxyurea, in an overlapping candidate region on OAR 5 (Table 4 ). Hydroxyurea can inhibit ribonucleotide reductase (RR) and is retained at high concentrations in tissues of various mammalian species including sheep 56 . Compared to viral or bacterial ribonucleotide reductase, the mammalian RR is less susceptible to inhibition by hydroxyurea 56 .…”

The Cell Killing Mechanisms of Hydroxyurea

“…The effectiveness for management of refractory psoriasis is likely due to its inhibitory effect on epithelial proliferation, which restores the patients’ thickened epidermis to a more normal appearance [10]. Interestingly, endogenous HU has been found in the plasma and various tissues of many animal groups [27], including humans [28], which is likely produced by arginase from the intermediate of nitric oxide synthesis pathway hydroxyarginine. Because the concentrations of endogenous HU vary by as much as 25 folds between tissues, and the concentrations in certain types of tissues are high enough to be effective against bacterial or viral infections, HU could also act as a natural defense agent.…”

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

“…The inhibition appears to proceed through the free radical nitroxide metabolite of hydroxyurea, which quenches the tyrosyl free radical at the active site of the M2 protein subunit of the enzyme [ 190 , 191 ]. Hydroxyurea is also used in the treatment of sickle cell anemia and thalassemia intermedia, by increasing fetal hemoglobin synthesis which reduces the polymerization of sickle cell hemoglobin and the level of RBC transfusions, respectively [ 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 ]. Hydroxyurea has been recently identified as a natural product with possible antiviral and other applications [ 201 , 202 , 203 ].…”