Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts.
The metabolic and growth inhibitory effects of adenosine toward the human lymphoblast line WI-L2 were potentiated by the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and coformycin. EHNA, 5 micron, or coformycin, 3.5 micron, at concentrations that inhibited adenosine deaminase activity more than 90% had little effect on cell growth or the metabolic parameters studied. Adenosine, 50 micron, plus EHNA, 5 micron, arrested cell growth in both parent and adenosine kinase-deficient lymphoblasts, implicating the nucleoside as the mediator of the cytostatic effect. Adenosine, 50 micron, in combination with the adenosine deaminase inhibitors reduced 14CO2 generation from [1-14C]glucose by 38%, depleted 5-phosphoribosyl-1-pyrophosphate by more than 90%, and reduced pyrimidine ribonucleotide concentrations. Uridine, 10 or 100 micron, reversed adenosine plus EHNA growth inhibition in WI-L2 but not in adenosine kinase mutants. Adenine, 500 micron, which may be converted to the same intracellular nucleotides as adenosine, reduced the growth rate by 50% in both parent and adenine phosphoribosyltransferase-deficient lymphoblasts. Although adenine also depleted cells of 5-phosphoribosyl-1-pyrophosphate and reduced pyrimidine ribonucleotide by 50%, the mechanisms of adenine and adenosine toxicity differ. In contrast to the ability of uridine to reverse adenosine cytostasis, growth inhibition by adenine was not reversed by uridine, indicating that pyrimidine ribonucleotide depletion is not the primary mechanisms of adenine toxicity.
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000241:Adenosine / Q000494:pharmacology*; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D011742:Pyrimidine Nucleotides / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology; D014529:Uridine / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D001381:Azepines; D011742:Pyrimidine Nucleotides; D012263:Ribonucleosides; D010754:Phosphoribosyl Pyrophosphate; D000248:Adenosine Kinase; D000225:Adenine; D000241:Adenosine; D014529:Uridine