Urea, Urease, Cyanate, and the Sickling of Hemoglobin S

Abstract Urea in glucose solutions has been advanced as a chemotherapeutic agent in sickle cell disease because it has been found effective both in reversing and in blocking sickling. It has been suggested recently that this beneficial action of urea may be the result of formation of cyanate from urea and subsequent carbamylation of beta S globin chains in the hemoglobin S molecule. In this paper, we show that the urea molecule per se interferes with sickling. SS cells in oxygen-free atmosphere, protected from sickling by urea— sugar solutions, were sickled after urease was added. Urea blocks and reverses sickling; ureaprotected sickle cells become sickled after incubation with urease; these effects are reversible and immediate, and are apparent in the deoxygenated state. In contrast, cyanate blocks but does not reverse sickling; cyanate-treated cells are unaffected by urease; these effects are permanent and require time; and hemoglobin S must first be oxygenated before carbamylation will occur. Evidently, urea and cyanate interfere with sickling by distinctly separate molecular mechanisms. Possible mechanisms for the action of urea are discussed.