Deoxyribonucleoside toxicity in adenosine deaminase and purine nucleoside phosphorylase deficiency: implications for the development of new immunosuppressive agents.
The immunodeficient state associated with adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency may result from the selective phosphorylation by thymus-derived lymphocytes of the ADA substrate deoxyadenosine and the PNP substrate deoxyguanosine, leading to the intracellular trapping of toxic deoxyribonucleoside triphosphates. Agents such as deoxycytidine might be able to favourably modify the immunodeficient state by inhibiting deoxyribonucleoside phosphorylation. Deficiencies of other nucleotide catabolic enzymes, if selectively expressed by lymphocytes, might also lead to immunodeficiency via nucleoside trapping in lymphoid tissues. Purine deoxyribonucleoside analogues, either alone or in combination with ADA inhibitors, may have value as lymphospecific antimetabolites.
D000243:Adenosine Deaminase / Q000172:deficiency*; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology; D003602:Cytotoxicity, Immunologic; D003839:Deoxyadenosines / Q000494:pharmacology; D003849:Deoxyguanosine / Q000494:pharmacology; D003853:Deoxyribonucleosides / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology; D007166:Immunosuppressive Agents; D007942:Leukemia, Experimental / Q000201:enzymology; D009700:Nucleoside Deaminases / Q000172:deficiency*; D010430:Pentosyltransferases / Q000172:deficiency*; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency*; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology
D003839:Deoxyadenosines; D003853:Deoxyribonucleosides; D007166:Immunosuppressive Agents; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase; D003849:Deoxyguanosine