Cell entry and export of nucleoside analogues

Some nucleoside analogues currently used as antiretroviral agents might promote mutagenesis besides their putative ability to interfere with endogenous nucleotide metabolism and/or inhibit viral transcription. The intracellular concentration of nucleosides and nucleobases is to some extent the result of the metabolic background of the specific cell line used for infection studies, its particular suit of enzymes and transporters. This review focuses on the transporter-mediated pathways implicated in either the uptake or the efflux of nucleoside- and nucleobase-derivatives. From a biochemical point of view, four different types of transport processes for nucleoside-related antiviral drugs have been described: (1) equilibrative uniport, (2) substrate exchange, (3) concentrative Na+- or H+-dependent uptake and finally, (4) substrate export through primary ATP-dependent active efflux pumps. These mechanisms are mainly related to the following set of transporter families: Concentrative Nucleoside Transporter (CNT), Equilibrative Nucleoside Transporter (ENT), Organic Anion Transporter (OAT) and Organic Cation Transporter (OCT), Peptide Transporter (PEPT) and Multidrug Resistance Protein (MRP). The basic properties of these carrier proteins and their respective role in the transport across the plasma membrane of nucleoside-derived antiviral drugs are reviewed.