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

Journal of Cellular Physiology
C B ThomasE W Holmes

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--...Continue Reading

Citations

Oct 29, 1991·European Journal of Pharmacology·H H OeiA Y Jeng
Dec 1, 1985·The Journal of Clinical Investigation·Y Sidi, B S Mitchell
Oct 2, 2004·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Michael A MenzeSteven C Hand
Aug 1, 1985·Journal of Cellular Physiology·S ArcherV L Chan
Jan 4, 2019·Journal of Molecular Evolution·Ricardo Hernández-MoralesAntonio Lazcano
Jul 1, 1985·The American Journal of Physiology·L L MuldoonM L Villereal
Nov 1, 1990·Archives of Biochemistry and Biophysics·J BarankiewiczH E Gruber

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