ATP depletion as a consequence of adenosine deaminase inhibition in man.

Abstract

Hereditary deficiency of the enzyme adenosine deaminase (EC 3.5.4.4) results in an immunodeficiency syndrome characterized by a marked reduction in circulating lymphocytes. 2''-Deoxycoformycin, a potent inhibitor of adenosine deaminase, was administered to a patient with a lymphoproliferative malignancy. The clinical consequences of pharmacologic inhibition of adenosine deaminase activity included an abrupt decrease in the lymphocyte count, abnormalities of renal and hepatic function, and hemolytic anemia. The plasma concentrations of adenosine and deoxyadenosine rose to peak values of 13 .mu.M and 5 .mu.M, respectively, and erythrocyte dATP levels increased to 110 pmol/106 cells over 9 days. There was a corresponding decrease in erythrocyte ATP levels from 128 to < 6 pmol/106 cells. A similar profound reduction in ATP occurred in the erythrocytes of a 2nd patient. The rapid and unexpected depletion of ATP associated with dATP accumulation may account at least partly for the toxicity associated with 2''-deoxycoformycin administration. The inverse relationship of ATP and dATP raises major questions about the control of energy metabolism in erythrocytes.