Functional and mechanistic studies on the toxicity of deoxyguanosine for the in vitro proliferation and differentiation of human peripheral blood B lymphocytes.
Deoxyguanosine (dGuo) has been implicated as the toxic metabolite causing a severe impairment of cellular immunity in children with a genetic deficiency of purine nucleoside phosphorylase (PNP). In peripheral blood T cells of normal donors both the pathway which leads to phosphorylation of dGuo (ultimately resulting in deoxyguanosine triphosphate, dGTP) and the salvage pathway which starts with degradation of dGuo by PNP (resulting in the formation of guanosine triphosphate, GTP) contribute to the inhibition of proliferation. In normal peripheral blood B cells, addition of dGuo leads to an inhibition of proliferation and differentiation. The concentrations of dGuo needed to cause a 50% inhibition are equivalent for peripheral blood T cells and B cells. Inhibition of B cell differentiation can be observed at the level of intracytoplasmic as well as secreted Ig and concerns all Ig isotypes. The early phase of B cell activation which takes place during a 24-h preculture with formalinized Cowan I Staphylococci is not affected by dGuo; it is not until proliferation and differentiation of B cells, brought about by culturing in the presence of crude concanavalin A supernatant, occurs that inhibitory effects of dGuo become evident. Addition of dGuo to B cell cultures results in an intracellular accumulation of GTP and dGTP. Addition of 8-aminoguanosine, a PNP inhibitor, next to dGuo, completely prevents the dGuo-mediated inhibition. Under these circumstances the dGuo-mediated increase in intracellular GTP is abrogated while dGTP accumulation still occurs. This indicates that the inhibitory effect of dGuo on the proliferation and differentiation of peripheral blood B lymphocytes of normal donors is independent of dGTP accumulation.
D000225:Adenine / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000494:pharmacology; D003849:Deoxyguanosine / Q000633:toxicity*; D003854:Deoxyribonucleotides / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors; D013211:Staphylococcus aureus / Q000276:immunology
D003854:Deoxyribonucleotides; D007042:Hypoxanthines; D003841:Deoxycytidine; D019271:Hypoxanthine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine; D000225:Adenine