D. HOROWITZc, ARIEH RUBINSTEINd

The inherited deficiency of adenosine deam- inase (adenosine aminohydrolase; EC 3.5.4.4) activity in humans is associated with an immunodeficiency. Some of the immu- nodeficient and enzyme-deficient patients respond immu- nologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously re- ported that erythrocytes and lymphocytes from immunodefi- cient and enzyme-deficient children contained increased con- centrations of ATP, and in the one child studied after erythro- cyte infusion therapy, the intracellular level of ATP diminished. Using high-pressure liquid chromatography that resolves ATP and 2'-dATP, we have observed greater than 50-fold elevations of dATP in the erythrocytes of immunodeficient, adenosine deaminase-deficient patients but not in the erythrocytes of an immunocompetent adenosine deaminase-deficient patient. The erythrocyte dATP in two unrelated adenosine deaminase-de- ficient, immunodeficient patients disappeared after infusion of normal erythrocytes. We propose that deoxyadenosine, a substrate of adenosine deaminase, is the potentially toxic sub- strate in adenosine deaminase deficiency, and that the mediator of the toxic effect is dATP, a recognized potent inhibitor of ri- bonucleotide reductase.