PHARMACOLOGY OF CYANATE. I. GENERAL EFFECTS ON EXPERIMENTAL ANIMALS

¹ The Rockefeller University, New York and the Departments of Pediatirics and Medicine, Cornell University Medical College, New York, New York

The development of cyanate as an antisicklimg drug in the treatment of sickle cell disease necessitated an investigation of its effect on experimental animals. The LD₃₀ for a single i.P. injection of NaNCO and KNCO 260 and 320 mg/kg, respectively. The i.p. injection of KNCO (32 mg/kg) to mice once daily (five times a week) for a five-month period had no adverse effects. In addition, sodium cyanate was administered orally to dogs (100 mg/kg of NaNCO) and monkeys (100 mg/kg of NaNCO) for a 15-month period without any apparent ill effects being observed. In fact, the only measurable difference between the control animals and the animals receiving cyanate was an increase in the oxygen affinity of the blood of all the species receiving cyanate. Although this change in the P₅₀, of the blood is quite dranmatic, no physiological or pathological sequelae have been observed in animals receiving cyanate. The specificity of the cyanate for the NH₂-terminal valine of hemoglobin is quite striking. Continuous cyanate administration leads to an accumulation of 1 carbamyl group per hemoglobin tetramer with no measurable carbamylation of the -amino groups of lysine residues of hemoglobin. The injection of 10 µmol of ¹⁴C-cyanate to a mouse Produced the following distribution of radioactivity : 72% broken down to CO₂, 7% in the urine, 7.5% as a specific carbamylation of the NH₂-terminal valine of hemoglobin, 3.3% in bones. 2.1% in muscle, and less than 3% in all the other organs. The chronic administration of cyanate leads to an accumulation of carbamyl groups on the hemoglobin and in other organs although the number of carbamyl groups in all the various compartments eventually plateaus after different periods of time. The similarity in structure and reactivity of CO₂ and cyanate probably accounts for the specificity of cyanate for the NH₂-terminal valine of hemoglobin. It is thus possible to achieve 1 carbamyl group per hemoglobin tetramer without seriously affecting the well-being of the species studied.

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