Metabolism of EICAR (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide), a potent inhibitor of inosinate dehydrogenase.
The cytostatic agent 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) causes a rapid and marked inhibition of inosinate (IMP) dehydrogenase activity in intact tumor cells. [3H]EICAR is metabolised in L1210 cells to its 5'-mono-, 5'-di- and 5'-triphosphate in a concentration-dependent manner. The metabolites accumulate proportionally with the initial extracellular EICAR concentrations (ranging from 0.25 to 200 microM). The nicotinamide adenine dinucleotide (NAD) analogue of EICAR, designated EAD, also accumulates within the cells and becomes the major metabolite after 48 hr incubation with 5 microM [3H]EICAR. EAD has a markedly longer intracellular half-life than EICAR 5'-mono-, 5'-di- and 5'-triphosphate. An additional EICAR metabolite elutes on an anion exchange Partisphere SAX HPLC chromatogram between EICAR 5'-di- and 5'-triphosphate. Its intracellular levels are approximately 10-fold lower than those of EAD and the nature of this metabolite has still to be identified. The differential role of EAD and EICAR 5'-monophosphate in the inhibition of IMP dehydrogenase is currently under investigation.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Stet
L
L
Matsuda
A
A
Wiebe
L
L
Knauss
E
E
De Clercq
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice; D012263:Ribonucleosides / Q000378:metabolism* / Q000493:pharmacokinetics; D014316:Tritium; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012263:Ribonucleosides; D014316:Tritium; C059077:5-ethynyl-1-ribofuranosylimidazole-4-carboxamide; D007168:IMP Dehydrogenase