Abstract
Deoxyguanosine (dGR) and deoxyadenosine (dAR) accumulate in PNP and ADA deficiency, associated respectively with T cell immunodeficiency or SCID. Conflicting hypotheses have been invoked from in vitro studies to explain this differential toxicity. It was originally proposed that T cells, but not B cells, could accumulate high dGTP and dATP levels because of a much higher kinase, but lower 5′-nucleotidase in T cells. In vitro studies of dGR toxicity have frequently used very high substrate levels and been complicated by the lack of an effective PNP inhibitor. Several reports have shown that the toxicity demonstrated related to GTP rather than dGTP accumulation.
we used guanosine (GR) to inhibit PNP and have investigated the metabolism of [ [14C]dGR in peripheral blood cells in vitro at levels approximating those found in vivo in PNP deficiency. We found that thymocytes accumulated some dGTP even without inhibitor and high levels of dGTP following PNP inhibition. Moreover, they were the only cells to do so to any significant degree. This contrasts with our studies using dAR which showed dATP accumulation by both thymocytes and B cells. The exclusive ability of thymocytes to accumulate dGTP provides a logical explanation for the selective toxicity to T cells in PNP deficiency. The rapid metabolism of dGR to GTP in the absence of inhibition, and subsequent effects of GTP on cell metabolism, may also account for the differing results reported in toxicity studies using low versus high dGR concentrations.
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Anne Simmonds, H., Taddeq, A., Fairbanks, L. et al. 143 DeoxyGTP ACCUMULATES IN THYMOCYTES, BUT NOT IN T OR B LYMPHOCYTES IN SIMULATED PNP DEFICIENCY. Pediatr Res 24, 135 (1988). https://doi.org/10.1203/00006450-198807000-00167
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DOI: https://doi.org/10.1203/00006450-198807000-00167