Abstract
The accumulation of deoxyadenosine (dAdo) and its metabolites may produce immunodeficiency in children who lack adenosine deaminase. The metabolism of dAdo in dividing human lymphoblasts, and the mechanism of dAdo toxicity, have aroused considerable controversy. To investigate this problem, we have selected stable mutant human lymphoblastoid cell lines resistant to the anti-proliferative effects of dAdo and have compared their biochemical phenotypes. The dAdo-resistant mutants differed from wild type cells in one of three ways: (1) an increase in the activity of ribonucleotide reductase, (2) an increase in cytoplasmic nucleotidase activity, (3) a decrease in deoxycytidine kinase activity. All three genetic changes caused a secondary rise in de novo deoxycytidine formation and excretion, and a reciprocal inability to phosphorylate dAdo and to form dATP. Thus, human lymphocytes can avert dAdo toxicity by increasing deoxycytidylate synthesis and degradation, as well as by decreasing deoxycytidine kinase levels. The net result in each case is an impaired functional capacity to phosphorylate deoxyadenosine.
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Carson, D., Kubota, M., Wasson, D. et al. GENETIC ANALYSIS OF DEOXYADENOSINE TOXICITY IN DIVIDING HUMAN LYMPHOBLASTS: 29. Pediatr Res 19, 748 (1985). https://doi.org/10.1203/00006450-198507000-00049
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DOI: https://doi.org/10.1203/00006450-198507000-00049
