Selective reduction of intracellular guanosine 5'-triphosphate pool by 4-carbamoylimidazolium 5-olate in murine tumor cells.
Ehrlich carcinoma and P388 leukemia cells were rendered resistant to 4-carbamoylimidazolium 5-olate (SM-108), and assessments were made of biochemical and pharmacological determinants for the sensitivity to SM-108 using both sensitive and resistant sublines. We observed that the treatment of cells with SM-108 in vitro caused a remarkable decrease in the intracellular guanosine 5'-triphosphate pool level in sensitive but not in resistant sublines. There was no difference in the ability to take up SM-108 between sensitive and resistant sublines, but the cellular conversion of SM-108 to its nucleotide, which is the putative active anabolite of SM-108, proceeded only in sensitive sublines. Enzymological studies revealed that the activity of adenine phosphoribosyltransferase (EC 2.4.2.7), which is believed to conjugate SM-108 with 5-phospho-alpha-D-ribose 1-diphosphate, was very low in the resistant sublines. These results strongly support our previous hypothesis that SM-108 is activated by adenine phosphoribosyltransferase to SM-108-nucleotide which then inhibits hypoxanthine-5'-monophosphate dehydrogenase (EC 1.2.1.14), a key enzyme for the de novo synthesis of guanosine 5'-monophosphate.
Fukui
M
M
Inaba
M
M
Tsukagoshi
S
S
Sakurai
Y
Y
D000228:Adenine Phosphoribosyltransferase / Q000378:metabolism; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism; D002460:Cell Line; D004351:Drug Resistance; D006160:Guanosine Triphosphate / Q000378:metabolism*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology*; D007941:Leukemia P388 / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism
D007093:Imidazoles; C028138:5-carbamoyl-1H-imidazol-4-yl-piperonylate; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D000228:Adenine Phosphoribosyltransferase; C033758:4-carbamoylimidazolium 5-olate