A model for adenosine transport and metabolism

1. A model is presented for adenosine transport and metabolism in different steady states. The model considers steady-state equations for metabolic enzymes based on information from the literature on their kinetic behaviour. 2. Assuming that extracellular adenosine and inosine are translocated by three transporters, we have devised rate equations for these nucleoside transporters which are valid when both nucleosides are present. Since the Na(+)-independent transporter can either incorporate nucleosides into the cell or release them, various conditions have been simulated in which inosine was either incorporated or released. 3. Control analyses are reported which show that the fluxes towards intracellular adenine nucleosides are controlled by ecto-5′-nucleotidase in some circumstances and by the nucleoside transporters in others. The nucleoside transporter is responsible for five fluxes (two Na+ dependent adenosine transport mechanisms, a Na(+)-dependent inosine transport, a Na(+)-independent adenosine transport and a Na(+)-independent inosine influx or efflux) but the control is not always positive for all these fluxes. The control patterns of these five fluxes indicate that, in the presence of extracellular adenosine and inosine, the intracellular metabolism of adenine derivatives would be highly dependent on the extracellular and intracellular concentrations of both nucleosides, on the ectoenzymes (5′-nucleotidase and adenosine deaminase) and on the transporter. 4. Predictions of the model were examined. The results indicate that a change in one independent variable (extracellular AMP concentration) makes the system evolve towards a new steady state which is far from the initial one and has a different control pattern. In contrast, simulation of inhibition of the carriers produces only slight modification of the fluxes since the concentrations of the metabolites change to counteract the effect. Thus, for instance, a 50% inhibition of the three carriers does not affect the flux towards intracellular adenine nucleotides. Finally, our model has confirmed that the evolution of the concentration of extracellular adenosine, when an increase in extracellular AMP is produced, agrees with the behaviour expected for a neurohormone.