Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency

A. Cohen, R. Hirschhorn, S. D. Horowitz, A. Rubinstein, S. H. Polmar, R. Hong, D. W. Martin

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Abstract

The inherited deficiency of adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in humans is associated with an immunodeficiency. Some of the immunodeficient and enzyme-deficient patients respond immunologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously reported that erythrocytes and lymphocytes from immunodeficient and enzyme-deficient children contain increased concentrations of ATP, and in the one child studied after erythrocyte 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-deficient, immunodeficient patients disappeared after infusion of normal erythrocytes. We propose that deoxyadenosine, a substrate of adenosine deaminase, is the potentially toxic substrate in adenosine deaminase deficiency, and that the mediator of the toxic effect is dATP, a recognized potent inhibitor of ribonucleotide reductase.

Original languageEnglish (US)
Pages (from-to)472-476
Number of pages5
JournalUnknown Journal
Volume75
Issue number1
DOIs
StatePublished - Jan 1 1978
Externally publishedYes

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    Cohen, A., Hirschhorn, R., Horowitz, S. D., Rubinstein, A., Polmar, S. H., Hong, R., & Martin, D. W. (1978). Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. Unknown Journal, 75(1), 472-476. https://doi.org/10.1073/pnas.75.1.472