Hydroxyurea (therapeutics and mechanism): metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling and clinical applications.

During a century, hydroxyurea has received much attention in relation to its physiological properties. This review mainly deals with the metabolism, mechanism, cell signaling, therapeutic properties, bioactivity, receptors, and toxicity. Metabolism provides insight concerning the mechanism. Carbamoyl nitroso is an intermediate, based on ease of oxidation of the parent and subsequent formation of nitroxyl and nitric oxide. Carbamoyl nitroso bears structural and electrochemical similarity to acyl nitroso from hydroxamic acids, to the phenylhydroxylamine-nitrosobenzene couple, and to α-dicarbonyls. Carbamoyl nitroso may be involved in electron transfer, reactive oxygen species formation, and oxidative stress. Cell signaling plays a significant role in the biological action. The therapeutic properties are discussed with emphasis on cancer, sickle cell disease, HIV, skin, and genes. Promise as a practical medicine is indicated by clinical trials. Toxicity is also included. Carbamoyl nitroso, nitroxyl, nitric oxide, and metal complexes of the parent drug are designated the main actors in the physiological effects. The mechanistic theme is in keeping with prior reports in Medical Hypotheses.