Transport Mechanisms of Nucleosides and Nucleoside Analogues ReverseTranscriptase Inhibitors in the Brain

Because of their hydrophilic natures, movements of nucleosides and many of their analogues across cellular membranes are mediated by nucleoside transporter (NT) proteins. Thus, NT proteins play an important role in physiological actions of nucleosides and in alterations of their function under various pathophysiological conditions. Also, these proteins are important for the therapeutic actions of some of synthetic nucleosides that have pharmacological actions and are thus used as drugs, including nucleoside analogues reverse transcriptase inhibitors (King et al., 2006, Zhang et al., 2007). Before the “molecular biology” era, it was possible to explore nucleoside transport processes mainly by functional transport studies, which measured transcellular flux or cellular uptake of radiolabelled nucleosides. These early studies have identified two distinct transport processes in mammalian cells: the equilibrative bidirectional transport with lower affinity for naturally occurring nucleosides and the concentrative, unidirectional secondary active transport (Na+/nucleoside cotransport) which revealed higher affinity for nucleosides (Hyde et al., 2004, Baldwin et al., 2004). Also, based on inhibition of these processes by synthetic analogues and based on substrate specificity and kinetics, it was recognized that both groups were heterogeneous: equilibrative nucleoside transport processes were further categorized as either nitrobenzylthioinosine (NBMPR)-sensitive (es) or NBMPR-insensitive (ei), while concentrative transport processes were categorized as either cit (concentrative, NBMPR insensitive, thymidine important substrate), cif (concentrative, NBMPR insensitive, formycin B important substrate) or cib (concentrative, NBMPR insensitive, broadly selective for purine and pyrimidine nucleosides) (Cass et al., 1998). Transport studies have also revealed that all these transport processes are not ubiquitously distributed in all mammalian cells; while equlibrative transport processes were more or less ubiquitous, concentrative transport processes were mainly found in epithelia, endothelial layers and in the liver (for an early review of nucleoside transport processes see Young and Jarvis 1983). Development of molecular biology techniques has allowed identification of the proteins responsible for nucleoside transport processes (King et al., 2006). Purification and N-terminal sequencing of the es transporter from human erythrocytes enabled cloning a human placental