Abstract
The C-8 substituted guanine nucleosides are a new class of immunologically active purine analogues. Naturally occurring guanosine is immunosuppressive to B-cells. 8-Mercaptoguanosine (8-SGuo) and 8-bromoguanosine (8-BrGuo) have polyclonal B-cell activating properties in murine lymphocytes. 8-Aminoguanosine (8-NH Guo) has no immunologic effects on cells in culture but is a potent inhibitor of the purine catabolic enzyme, purine nucleoside phosphoylase. This study examined the metabolic fate of guanosine and the C-8 substituted analogues in dialyzed human splenic cytosol. Required cofactors for the involved enzyme systems were added to the cytosol. The metabolism of the ribonucleoside substrate to other purine forms was monitored by reverse-phase and anion exchange HPLC at 15 minute intervals for 2 hours. Guanosine declines linearly over 90 minutes with linear accumulations in guanine, xanthine, GTP and GDP when incubated at 37°C in the presence of PRPP. 8-SGuo and 8-BrGuo remain essentially non-metabolized to other forms after 120 minutes. 8-NH Guo is rapidly metabolized to 8-NH guanine and a minor peak of 8-NH GDP appearing after 60 minutes. These preliminary studies in human spleen demonstrate that 2 C-8 substituted purine analogues (8-SGuo and 8-BrGuo) that stimulate B-cell proliferation and differentiation are not substantially metabolized by cytoplasmic purine enzymes. Conversely guanosine is extensively metabolized to both higher (GTP and GDP) and lower (guanine and xanthine) forms. These findings may help define the molecular basis for both immune-suppressive and immune-potentiating effects of guanosine and its C-8 substituted analogues.
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Lawrence Edwards, N., Mond, J. 29 METABOLISM OF CUANOSINE AND ITS C-8 SUBSTITUTED ANALOGUES IN HUMAN LYMPHOCYTE CYTOPLASM. Pediatr Res 24, 116 (1988). https://doi.org/10.1203/00006450-198807000-00053
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DOI: https://doi.org/10.1203/00006450-198807000-00053