Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency

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

Research output: Contribution to journalArticle

270 Citations (Scopus)

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
JournalProceedings of the National Academy of Sciences of the United States of America
Volume75
Issue number1
StatePublished - 1978
Externally publishedYes

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Poisons
Adenosine Deaminase
Erythrocytes
Adenosine Triphosphate
Ribonucleotide Reductases
Enzymes
2'-deoxyadenosine
triphosphoric acid
Severe combined immunodeficiency due to adenosine deaminase deficiency
Human Activities
High Pressure Liquid Chromatography
Lymphocytes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. / Cohen, A.; Hirschhorn, R.; Horowitz, S. D.; Rubinstein, Arye; Polmar, S. H.; Hong, R.; Martin, D. W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 75, No. 1, 1978, p. 472-476.

Research output: Contribution to journalArticle

Cohen, A. ; Hirschhorn, R. ; Horowitz, S. D. ; Rubinstein, Arye ; Polmar, S. H. ; Hong, R. ; Martin, D. W. / Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. In: Proceedings of the National Academy of Sciences of the United States of America. 1978 ; Vol. 75, No. 1. pp. 472-476.
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AU - Hong, R.

AU - Martin, D. W.

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