Expression of deoxyadenosine and deoxyguanosine toxicity at different stages of lymphocyte activation.
We have previously shown that deoxyguanosine (dGuo) is toxic to normal T and B lymphocytes, an effect mediated by intracellular accumulation of guanine ribonucleotides. In order to define the cellular processes that are sensitive to guanosine triphosphate (GTP) we have performed studies in which the effects of dGuo on normal T cells are compared with those of deoxyadenosine (dAdo) on adenosine deaminase (ADA)-deficient T cells. Kinetic studies show that dAdo exerts its toxic effects on processes that precede the onset of DNA synthesis, like interleukin 2 receptor expression, whereas dGuo added as late as 24-48 h after initiation of the culture still inhibits mitogen-induced proliferation. It can thus be concluded that dGuo toxicity as mediated through guanine ribonucleotides is manifested relatively late during the process of T-cell activation, whereas dAdo acts early in T-cell activation by a mechanism that cannot be explained by inhibition of ribonucleotide reductase.
D000328:Adult; D003839:Deoxyadenosines / Q000633:toxicity*; D003849:Deoxyguanosine / Q000633:toxicity*; D004306:Dose-Response Relationship, Immunologic; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D010835:Phytohemagglutinins; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000187:drug effects; D015375:Receptors, Interleukin-2
D003839:Deoxyadenosines; D007376:Interleukin-2; D010835:Phytohemagglutinins; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D006151:Guanosine; C032533:8-aminoguanosine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine