PMC:2678986 / 28760-32819 JSONTXT

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,"span":{"begin":4053,"end":4057},"obj":"18042828"},{"id":"19176219-18042828-3577010","span":{"begin":4053,"end":4057},"obj":"18042828"}],"text":"4.3 Nucleoside transporters\nThere are two main types of nucleoside transporters, classified as low-affinity equilibrative (SLC29) and high-affinity concentrative (SLC28), which are known to transport certain NRTIs.\n\n4.3.1 Equilibrative nucleoside transporters (ENTs)\nThere are four members of the SLC29 family. hENT1, the first characterised family member, shares similar substrate specificities with hENT2. These transporters play a pivotal role in the uptake of nucleoside and nucleobases across a membrane down their concentration gradient. Based on their sensitivity to nitrobenzythioinosine, ENTs are subdivided into equilibrative sensitive (es) and equilibrative insensitive (ei) (Baldwin et al., 2004; Thomas, 2004).\nENT1 protein, which encodes the es nucleoside transporter, is present on the human BBB. It is thought that this carrier is responsible for the transport of ddI across the guinea pig BBB. This was confirmed when the es transporter substrates, adenosine and thymidine, inhibited the brain uptake of [3H]ddI (Gibbs et al., 2003a). Interestingly, the es transporter is also active in human lymphocytes, raising the possibility that it could facilitate the transport of NRTIs into this HIV reservoir (Chan et al., 1993). ENT2, the ei transporter, transports purine and pyrimidine nucleosides but with a lower affinity that ENT1. However unlike ENT1, ENT2 is a carrier of AZT and can transport ddI and ddC much more efficiently than ENT1 (Baldwin et al., 2004).\nRecently, Minuesa et al. (2008) found that human ENTs were the most highly expressed transporters in peripheral blood mononuclear cells and CD4+ T-cells and that the expression and activity of this transporter were increased by 100- and 30-fold, respectively, following stimulation of primary T lymphocytes. Determining the isoform responsible for anti-HIV drug transport across cell membranes would prove valuable in targeting these drugs to infected cells and in understanding drug–drug interactions and therapy failure (Minuesa et al., 2008).\n\n4.3.2 Concentrative nucleoside transporters (CNTs)\nThere are three subtypes of sodium-dependent CNTs (CNT1–3) in the SLC28 family. CNT1 is a pyrimidine specific transporter whereas CNT2 is a purine-preferring transporter which also has the ability to transport uridine. CNT3 is a broad selective nucleoside transporter (Gray et al., 2004). These transporters have been identified in the liver, intestine, kidney and choroid plexus. Redzic et al. (2005) demonstrated the presence of rENT1, rENT2 and rCNT2 mRNA and protein in primary cultures of rat brain endothelial cells and rat choroid plexus epithelial cells. rCNT3 was present at the transcript level in choroid plexus epithelium. Furthermore, they showed that the concentrative transport of nucleosides was associated exclusively with the membrane that faces brain fluids in situ, suggesting a role of these barriers in extruding nucleosides from the brain (Redzic et al., 2005).\nUsing rat and human tissues, CNT and ENT cDNAs were cloned and their functional characterisation was determined using Xenopus oocytes. This study revealed that CNT1, CNT3 and ENT2 but not CNT2 or ENT1 transported AZT but with a much lower affinity than endogenous nucleosides. In addition, the influx of AZT into the CSF through choroid epithelial cells was found to be unaffected by endogenous nucleosides (Yao et al., 2001; Strazielle et al., 2003). CNT has also been implicated in the transport of ddI across the BBB (Li et al., 2001). However, the role of human CNT1 as a uptake transporter for ddI and stavudine (d4T) has remained controversial, as some researchers have described such a function for hCNT1 whereas others (Minuesa et al., 2008; Chishty et al., 2004; Chang et al., 2004; Cano-Soldado et al., 2004) have argued that hCNT1/2 (and even hENT1) have a low affinity for these drugs due to the absence of the 3′OH group in the ribose ring of the structure of nucleoside analogs. Conversely, hCNT3 appears to be an efficient transporter of AZT, ddC and ddI (Minuesa et al., 2008)."}