Role of the nucleoside transport function in the transport and salvage of purine nucleobases.
Genetic deficiencies in the nucleoside transport function markedly altered the abilities of cultured mutant S49 T lymphoblasts to transport, incorporate, and salvage exogenous hypoxanthine. The concentrations of exogenous hypoxanthine required to reverse azaserine toxicity and replenish azaserine-depleted nucleoside triphosphate pools in AE1 cells, a nucleoside transport-deficient clone, were about 10-fold higher than those required for wild type cells. In a similar fashion, guanine could reverse mycophenolic acid toxicity in wild type but not in AE1 cells. Surprisingly, a second nucleoside transport-deficient clone, 80-5D2, which had lost 80-90% of its ability to transport nucleosides, required lower hypoxanthine concentrations than the wild type parent to reverse these azaserine-mediated effects. The addition of submicromolar concentrations of either p-nitrobenzylthioinosine or dipyridamole, two potent inhibitors of nucleoside transport, to wild type cells mimicked the phenotype of the AE1 cells with respect to hypoxanthine. AE1 cells or p-nitrobenzylthioinosine-treated wild type cells could only transport hypoxanthine at 10-25% the rate of untreated wild type cells, whereas 80-5D2 cells could transport hypoxanthine more efficiently. Adenine transport was also diminished in AE1 and FURD-80-3-6 cells, but not to sufficiently low levels to interfere with their ability to salvage adenine to overcome azaserine toxicity. These studies on S49 cells altered in their nucleoside transport capacity provide powerful genetic evidence that purine nucleobases share a common transport function with nucleosides in these mammalian T lymphoblasts.
D000225:Adenine / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001377:Azaserine / Q000494:pharmacology; D001692:Biological Transport; D002460:Cell Line; D004176:Dipyridamole / Q000494:pharmacology; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D051379:Mice; D009705:Nucleosides / Q000378:metabolism*; D011687:Purines / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D007042:Hypoxanthines; D009705:Nucleosides; D011687:Purines; D019271:Hypoxanthine; D013868:Thioinosine; D004176:Dipyridamole; D001377:Azaserine; C001789:4-nitrobenzylthioinosine; D000225:Adenine