Aminoimidazole carboxamide ribonucleoside toxicity: A model for study of pyrimidine starvation

Abstract

Aminoimidazole carboxamide ribonucleoside (AIC-R), a purine precursor, has biphasic effects on the growth of Chinese hamster fibroblasts. At 200 microM AIC-R cell growth is almost completely arrested, while at 50 and 700 microM AIC-R cell growth is comparable to that observed in the absence of nucleoside. The growth inhibition produced by AIC-R is the consequence of inhibition of the orotate phosphoribosyltransferase-orotidylic decarboxylase (OPRT-ODC) reactions, as evidenced by a 87% reduction in the intracellular concentrations of UTP and CTP, accumulation of orotate in the medium, and restoration of normal growth by inclusion of 100 microM uridine in the medium. Inhibition of pyrimidine nucleotide synthesis at 200 microM AIC-R is associated with an 82% reduction in the intracellular concentration of PP-ribose-P and a 150% increase in the concentration of purine nucleotides. Restoration of cell growth to a normal rate at 700 microM AIC-R--a condition under which PP-ribose-P remains depressed and purine nucleotide concentrations are also depressed (40% of control)--and absence of toxicity at 50 microM AIC-R--a condition under which purine nucleotide concentrations are increased by 150% and PP-ribose-P concentration is normal--suggest that the inhibition of OPRT-ODC observed at 200 microM AIC-R is caused by the combination of the reduction in PP-ribose-P and increase in purine nucleotides. These studies provide a better understanding of the control of the OPRT-ODC reactions in the cell and provide additional insight into the basis of pyrimidine starvation induced by purine nucleosides.

Augmentation of Reduced Folate Carrier-Mediated Folate/Antifolate Transport through an Antiport Mechanism with 5-Aminoimidazole-4-Carboxamide Riboside Monophosphate

“…8). The rapid metabolism of AICAR to ZMP as assessed by HPLC is consistent with what has been observed by other investigators (Thomas et al, 1981). Of interest were the observations that after cells had accumulated ZMP, and AICAR was removed or 5-iodotubercidin was added, the intracellular ZMP level rapidly decreased and the augmentation of folate transport was reversed.…”

Z-nucleotide accumulation in erythrocytes from Lesch-Nyhan patients.

“…Z-riboside has been shown to be toxic to cultured fibroblasts at a concentration of200 ,M while lower and higher concentrations had far less effect (14). Growth inhibition at this concentration appeared to be mediated by inhibition of pyrimidine biosynthesis.…”

Effects of Stimulation of AMP-activated Protein Kinase on Insulin-like Growth Factor 1- and Epidermal Growth Factor-dependent Extracellular Signal-regulated Kinase Pathway

“…AICAR could affect de novo purine synthesis because ZMP is a natural intermediate in the pathway (26). In fact, AICAR was reported to inhibit the cell growth of Chinese hamster fibroblasts, and this was associated with a reduction of phosphoribosyl pyrophosphate and an increase in purine nucleotides (43). Thus, these subsidiary effects might be responsible for the partial inhibition by AICAR of the basal and EGF-dependent DNA synthesis in an Erk-independent manner (Fig.…”