Deoxycytidine Transport and Metabolism in the Central Nervous System

Abstract

The mechanisms by which deoxycytidine enters and leaves brain, choroid plexus, and CSF were investigated by injecting [3H]deoxycytidine intraarterially, i.v., and intraventricularly [i.vt.]. After intracarotid injection of deoxycytidine (1.0 .mu.M) into rats, deoxycytidine did not pass through the blood-brain barrier at a faster rate than sucrose. [3H]Deoxycytidine, either alone or together with unlabeled deoxycytidine, was infused at a constant rate into conscious adult rabbits. At 130 min, [3H]deoxycytidine readily entered CSF, choroid plexus, and brain. In brain, .apprx. 60% of the nonvolatile radioactivity was attributable to [3H]deoxycytidine phosphates. The addition of 0.22 mmol/kg unlabeled deoxycytidine to the infusion syringe decreased the phosphorylation of [3H]deoxycytidine in brain by .apprx. 50%; the addition of 2.2 mmol/kg of unlabeled deoxycytidine to the infusion syringe decreased the relative entry of [3H]deoxycytidine into CSF and brain by .apprx. 50 and .apprx. 75%, respectively. Two hours after the i.v. injection of [3H]deoxycytidine, [3H]deoxycytidine was rapidly cleared from CSF, in part, to brain, where approx. 65% of the [3H]deoxycytidine was converted to [3H]deoxycytidine phosphates. The i.v. injection of unlabeled deoxycytidine with the [3H]deoxycytidine decreased the phosphorylation of [3H]deoxycytidine in the brain significantly, and also decreased the clearance of [3H]deoxycytidine from the CSF. These results show that the entry of deoxycytidine from blood into CSF occurs by a saturable transport system within the choroid plexus. Once within the CSF, the deoxycytidine can enter brain, undergo phosphorylation to deoxycytidine phosphates, and subsequently be incorporated into DNA.