The effect of deoxyguanosine on human lymphocyte function. I. Analysis of the interference with lymphocyte proliferation in vitro.
The effect of deoxyguanosine on mitogen- and antigen-induced proliferation of peripheral blood lymphocytes from healthy donors was studied. Deoxyguanosine was found to inhibit the proliferative response to mitogens and antigens. Concentrations of deoxyguanosine causing 50% inhibition of the proliferation proved to be dependent on the activity of catabolic enzymes, such as purine nucleoside phosphorylase (PNP), in sera used in the culture media. The inhibitory effect of deoxyguanosine on phytohemagglutinin (PHA)-induced cell proliferation was prevented by deoxycytidine as well as by hypoxanthine. These findings were analyzed further by determination of intracellular (deoxy)-nucleotide levels. Stimulation of lymphocytes by PHA in the presence of deoxyguanosine leads to intracellular accumulation of dGTP. The presence of hypoxanthine in addition to deoxyguanosine abolished the inhibitory effect but did not prevent dGTP accumulation. On the other hand, the addition of deoxycytidine in combination with deoxyguanosine did not lead to intracellular accumulation of detectable amounts of dGTP, but only gave partial protection against the toxic effect. Furthermore, guanosine inhibited mitogen-induced cell proliferation to the same extent as did deoxyguanosine provided that the culture media were supplemented with pretreated fetal calf serum. Peripheral blood lymphocytes of a PNP-deficient or a HGPRT-deficient patient in cultures stimulated with PHA or pokeweed mitogen were resistant to the inhibitory effects of guanosine and were less sensitive to deoxyguanosine than cells of normal donors. The present results clearly show the involvement of two pathways contributing to deoxyguanosine-mediated inhibition of the proliferation of normal lymphocytes, i.e., on the one hand degradation of deoxyguanosine by PNP, salvage of guanine by HGPRT, and (possibly) phosphorylation of GMP eventually leading to GTP, and on the other hand formation of dGTP by direct phosphorylation of deoxyguanosine by deoxycytidine kinase.
D003841:Deoxycytidine / Q000494:pharmacology; D003849:Deoxyguanosine / Q000378:metabolism / Q000494:pharmacology*; D003854:Deoxyribonucleotides / Q000097:blood; D006801:Humans; D019271:Hypoxanthine; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency; D007042:Hypoxanthines / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011043:Pokeweed Mitogens / Q000494:pharmacology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000172:deficiency
D003854:Deoxyribonucleotides; D007042:Hypoxanthines; D007166:Immunosuppressive Agents; D010835:Phytohemagglutinins; D011043:Pokeweed Mitogens; D003841:Deoxycytidine; D019271:Hypoxanthine; D011683:Purine-Nucleoside Phosphorylase; D007041:Hypoxanthine Phosphoribosyltransferase; D003849:Deoxyguanosine