Alteration of purine metabolism by AICA-riboside in human B lymphoblasts.
The effect of 5-amino-4-imidazole-carboximide (AI-CA)-riboside on different pathways of purine metabolism (biosynthesis de novo, salvage pathways, adenosine metabolism, ATP catabolism) was studied in human B lymphoblasts (WI-L2). AICA-Riboside markedly decreased intracellular levels of 5-phosphoribosyl-1-pyrophosphate and in consequence affected purine biosynthesis de novo and purine salvage pathways. AICA-riboside inhibited incorporation of glycine into purine nucleotides, but when formate was used as the precursor of purine biosynthesis de novo, a biphasic effect was observed. The incorporation of formate into purine nucleotides was increased by AICA-riboside at concentrations up to 2 mM but decreased at higher concentrations. Salvage of the purine bases adenine, hypoxanthine, and guanine was markedly inhibited and utilization of extracellular adenosine in B lymphoblasts was reduced by AICA-riboside. AICA-riboside increased ribose 1-phosphate concentrations and increased degradation of prelabeled ATP. No effect on the intracellular levels of orthophosphate was found. Proliferation of WI-L2 lymphoblasts was only slightly affected at concentrations of AICA-riboside below 500 microM but markedly inhibited by higher concentrations.
Gensia Pharmaceuticals, Inc., Research Department, San Diego, California 92121.
J
J
Barankiewicz
R
R
Jimenez
G
G
Ronlov
M
M
Magill
H E
HE
Gruber
D000241:Adenosine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D012263:Ribonucleosides / Q000494:pharmacology* / Q000633:toxicity; D012267:Ribosemonophosphates / Q000378:metabolism
D011687:Purines; D012263:Ribonucleosides; D012267:Ribosemonophosphates; C031154:ribose 1-phosphate; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D010754:Phosphoribosyl Pyrophosphate; D000255:Adenosine Triphosphate; D000241:Adenosine