Inhibition of lymphoid cell growth by adenine ribonucleotide accumulation. The role of phosphoribosylpyrophosphate-depletion induced pyrimidine starvation.
The exact role of adenosine in the adenosine deaminase (EC 3.5.4.4) deficiency-related severe combined immunodeficiency disease has not been ascertained. We analysed the effects of adenosine, in the presence of the adenosine deaminase inhibitor, deoxycoformycin, on cell growth, cell phase distributions and intracellular nucleotide concentrations of cultured human lymphoblasts. Adenosine had a biphasic effect on cell growth and cell cycle distribution of a partial hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) deficient MOLT-HPRT cell line. After 24 h of incubation, 60 microM adenosine inhibited cell growth more extensively than did 100 and 200 microM adenosine. The distribution of the MOLT-HPRT cells in the various phases of the cell cycle showed a similar biphasic pattern. Adenosine concentrations in the medium below 10 microM caused accumulation of adenine ribonucleotides and depletion of phosphoribosylpyrophosphate, UTP and CTP in the cells. This was associated with inhibition of cell growth. Medium adenosine concentrations above 10 microM neither resulted in accumulation of adenine ribonucleotides nor in inhibition of cell growth.
D000241:Adenosine / Q000494:pharmacology*; D000243:Adenosine Deaminase / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency; D009700:Nucleoside Deaminases / Q000378:metabolism*; D010428:Pentosephosphates / Q000378:metabolism*; D015649:Pentostatin; D010754:Phosphoribosyl Pyrophosphate; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism*; D012263:Ribonucleosides / Q000494:pharmacology*; D012265:Ribonucleotides / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D058892:Adenosine Deaminase Inhibitors; D010428:Pentosephosphates; D011687:Purines; D011743:Pyrimidines; D012263:Ribonucleosides; D012265:Ribonucleotides; D003070:Coformycin; D015649:Pentostatin; D010754:Phosphoribosyl Pyrophosphate; D007041:Hypoxanthine Phosphoribosyltransferase; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase; D000241:Adenosine