S-adenosylhomocysteine hydrolase inactivation and purine toxicity in cultured human T- and B-lymphoblasts.
Accumulation of intracellular deoxyadenosine triphosphate and inactivation of the enzyme S-adenosylhomocysteine hydrolase by deoxyadenosine have been suggested as molecular mechanisms for lymphoid toxicity of inherited or acquired deficiency of adenosine deaminase. The relative roles of these two deoxyadenosine-mediated effects for lymphotoxicity have been explored by employing mutant human T- and B-lymphoblasts deficient in either adenosine kinase, deoxycytidine kinase, or both. At low concentrations (less than 25 mumol/L) of deoxyadenosine or ara-adenine, deoxycytidine kinase deficiency decreases growth sensitivity of human T-lymphoblasts to deoxyadenosine approximately fourfold, and to ara-adenine approximately twofold. Loss of both activities completely eliminates deoxyadenosine phosphorylation and cellular dATP accumulation, and decreases deoxyadenosine growth sensitivity approximately 200-fold and ara-adenine sensitivity approximately 80-fold. The inactivation by deoxyadenosine of intracellular S-adenosylhomocysteine hydrolase activity of human adenosine deaminase-deficient B-lymphoblasts and wild-type or deoxycytidine kinase-deficient T-lymphoblasts is comparable, despite the differing toxicity of this compound for these cell lines. Adenosine kinase deficiency in T-lymphoblasts results in resistance to 2'-deoxyadenosine--but not ara-adenine--associated inactivation of S-adenosylhomocysteine hydrolase, and this compound produces comparable degrees of inactivation of S-adenosylhomocysteine hydrolase in both the wild-type and double mutant cells, despite markedly different growth sensitivity. For B-lymphoblasts, 2'-deoxyadenosine together with adenosine produces comparable growth inhibition of wild-type and adenosine kinase-deficient cells, and this inhibition is more marked than with adenosine alone, but is independent of S-adenosylhomocysteine hydrolase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
D000248:Adenosine Kinase / Q000172:deficiency*; D043383:Adenosylhomocysteinase; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D002460:Cell Line; D003838:Deoxyadenine Nucleotides / Q000097:blood; D003839:Deoxyadenosines / Q000633:toxicity; D003842:Deoxycytidine Kinase / Q000172:deficiency*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D010770:Phosphotransferases / Q000172:deficiency*; D011684:Purine Nucleosides / Q000633:toxicity*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D014740:Vidarabine / Q000633:toxicity
D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D011684:Purine Nucleosides; D010770:Phosphotransferases; D000248:Adenosine Kinase; D003842:Deoxycytidine Kinase; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D014740:Vidarabine; C026600:2'-deoxyadenosine triphosphate