Protection by various deoxynucleosides against deoxyadenosine-induced DNA damage in adenosine deaminase-inactivated lymphocytes.
Adenosine deaminase deficiency is an inborn error resulting in immunodeficiency. The pathogenesis of the lymphopenia is not fully understood. Intracellular increases in dATP in the absence of deamination retard DNA repair in human resting lymphocytes and results in the slow accumulation of DNA strand breaks. We focused on the relationship between DNA damage and DNA precursor pools in cultures of deoxycoformycin-treated, ADA-inhibited resting lymphocytes. The addition of 10 microM deoxyadenosine led to a substantial number of DNA strand breaks within 12 h, breaks equivalent to those which occur with about 190 rad irradiation. Addition of any of the other deoxynucleosides used partially prevented this dAdo-induced DNA damage and promoted DNA repair. However, the preventive effects did not correlate inversely with intracellular dATP levels. Resting lymphocytes have very small dNTP pools. Treatment with dAdo slightly reduced dTTP and dCTP. Three kinds of deoxynucleosides, other than dAdo, restored or raised the corresponding dNTP level but the pool imbalance was only minimally corrected. Regarding the toxic effects of dAdo in ADA deficiency, not only dATP levels but also dNTP pool balance has a crucial role in the pathogenesis. Pool sizes of dTTP, dCTP, and possibly dGTP must be maintained at normal levels, if dAdo-induced DNA damage is to be avoided.
Shimoyama
R K
RK
Department of Pediatrics, Shimane Medical University, Izumo, 693-8051, Japan. rkana1@shimane-med.ac.jp
Seto
S
S
Mori
C
C
D058892:Adenosine Deaminase Inhibitors; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D003839:Deoxyadenosines / Q000378:metabolism* / Q000633:toxicity; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015649:Pentostatin / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D003839:Deoxyadenosines; D015226:Dinucleoside Phosphates; D004791:Enzyme Inhibitors; D015649:Pentostatin