Abstract
Deoxyadenosine (dAdo) is toxic at micromolar concentrations to adenosine deaminase inhibited resting human peripheral blood lymphocytes. 2-chlorodeoxyadenosine (CdA), a metabolically resistant dAdo congener, exhibits similar properties. Four hours of exposure to dAdo or CdA induced the accumulation of strand breaks in the DNA of normal resting lymphocytes, as measured by a DNA unwinding assay. The DNA damage was followed by consumption of NAD, probably mediated by increased poly(ADP-ribose) synthesis. The addition of 1-5mM nicotinamide prevented the dAdo and CdA triggered fall in NAD levels, and rendered the resting lymphocytes resistant to the toxic effects of both compounds. Both dAdo and CdA inhibited the repair of radiation induced DNA damage in resting lymphocytes, by impeding DNA polymerization. CdA was 100 fold more potent than dAdo. These results suggest that (i) a slow rate of DNA polymerization is required to maintain DNA integrity in resting human lymphocytes, (ii) dAdo and CdA inhibit polymerization, and cause DNA strand breaks to accumulate, (iii) the strand breakage triggers poly(ADP-ribose) synthesis, and causes lethal NAD depletion.
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Seto, S., Carrera, C., Wasson, D. et al. BIOCHEMICAL BASIS FOR DEOXYADENOSINE AND 2-CHLORODEOXYADENOSINE TOXICITY TO BESTING HDMAN LYMPHOCYTES: 187. Pediatr Res 19, 775 (1985). https://doi.org/10.1203/00006450-198507000-00207
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DOI: https://doi.org/10.1203/00006450-198507000-00207