IMP dehydrogenase catalyzes the rate-limiting reaction of de novo guanylate biosynthesis. Changes in IMP dehydrogenase activity have been implicated in the regulation of cell growth and differentiation. However, synthesis of guanine nucleotides is reported to be reduced by other differentiation inducers during cell maturation. We investigated here, the relationship between low intracellular GTP levels and differentiation induction using IMP dehydrogenase inhibitors including mycophenolic acid and mizoribine or all- trans retinoic acid. Treatment with IMP dehydrogenase inhibitors or all- trans retinoic acid induced morphologic, antigenic, and enzymatic differentiation in HL-60 and U937 cells. However, changes in intracellular GTP levels differed in each agent. The addition of mycophenolic acid resulted in a rapid decrease in intracellular GTP levels to 20-30% of control values which were then maintained at the lowest level during the culture period. Treatment with mizoribine decreased intracellular GTP levels to approximately 20-30% of controls for less than 24 h, then the GTP levels recovered to 50-60% and were maintained at that level. On the other hand, treatment with alltrans retinoic acid gradually decreased the intracellular GTP levels to approximately 80% of control values and induced maturation. Concurrent addition of guanosine abrogated IMP dehydrogenase inhibitors-induced differentiation, whereas all- trans retinoic acid-induced maturation was found to be independent of exogenous guanosine. Exposure to IMP dehydrogenase inhibitors for short period of time such as 24 h resulted in induction, whereas treatment for less than 12 h did not induce maturation. GTP levels reduced to approximately 20-30% of control for at least 24 h as a result of IMP dehydrogenase inhibitors may induce maturation, suggesting that differentiation induction by IMP dehydrogenase inhibitors differs from that by all-trans retinoic acid regarding intracellular GTP metabolism.
