ADENOSINE TRANSPORTERS

1. In mammals, nucleoside transport is an important determinant of the pharmacokinetics, plasma and tissue concentration, disposition and in vivo biological activity of adenosine as well as nucleoside analogues used in antiviral and anticancer therapies. 2. Two broad types of ade nosine transporter exist, facilitated diffusion carriers and active pr ocesses driven by the transmembrane sodium gradient. 3. Facilitated-di ffusion adenosine carriers may be sensitive (es) or insensitive (ei) t o nanomolar concentrations of the transport inhibitor nitrobenzylthioi nosine (NBMPR). Dipyridamole, dilazep and lidoflazine analogues are al so more potent inhibitors of the es carrier than the ei transporter in cells other than those derived from rat tissues. 4. The es transporte r has a broad substrate specificity (apparent K-m for adenosine simila r to 25 mu M in many cells at 25 degrees C), is a glycoprotein with an average apparent M(r) of 57,000 in human erythrocytes that has been p urified to near homogeneity and may exist in situ as a dimer, However, there is increasing evidence to suggest the presence of isoforms of t he es transporter in different cells and species, based on kinetic and molecular properties. 5. The ei transporter also has a broad substrat e specificity with a lower affinity for some nucleoside permeants than the es carrier, is genetically distinct from es but little informatio n exists as to the molecular properties of the protein. 6. Sodium depe ndent adenosine transport is present in many cell types and catalysed by four distinct systems, N1-N4, distinguished by substrate specificit y, sodium coupling and tissue distribution. 7. Two genes have been ide ntified which encode sodium dependent adenosine transport proteins, SN ST1 from the sodium/glucose cotransporter (SGLT1) gene family and the rat intestinal N2 transporter (cNT1) from a novel gene family includin g a bacterial nucleoside carrier (NupC). Transcripts of cNT1, which en codes a 648-residue protein, are found in intestine and kidney only. 8 . Success in cloning the remaining adenosine transporter genes will im prove our understanding of the diversity of nucleoside transport proce sses, with a view to better targeting of therapeutic nucleoside analog ues and protective use of transport inhibitors.