Thursday, February 18, 2010

Pharmacology of Nucleoside Transporter Proteins


Nucleic acid synthesis is a crucial role for cell and tissue growth. The nucleosides form an important component of gene synthesis and also have a major role in energy metabolism (ATP, GTP). Other prominent roles include signal transducer mechanisms in cells (cAMP, cGMP) and direct receptor mediated activity (Adenosine and Inosine) in a wide range of cellular events. Present day pharmacological therapy of Cancer and many Viral infections includes a number of nucleoside analogues - suggesting the myriad roles of these small molecules in these diseases.

Nucleosides are hydrophillic molecules and require a transporter for efficient transport across cell membranes and since synthesis of nucleotides is an energy draining process and possible only in a few types of cells, usually salvage and recycling is the predominant mode of nucleoside availability.

Nucleoside Transporters

There are two major families of nucleoside transporter proteins.

  1. SLC 28
    • Concentrative nucleoside transporters - CNT1,CNT2 and CNT3
    • Mediate unidirectional active, energy costly, sodium-dependent transport
    • high affinity for their substrates and more selective than ENT
  • hCNT1 is the pyrimidine- nucleoside preferring transporter
  • hCNT2 is a purine-nucleoside preferring transporter
  • hCNT3 shows much broader selectivity, translocating both purine and pyrimidine nucleosides
    • Initially thought to be expressed mostly in (re)absorptive epithelia, but now they are known to be broadly present in the body
      • CNT1 - specialized epithelial tissues such as small intestine, kidney and liver; virtually absent in most of the immune system cells
      • CNT2 in immune system cells is ubiquitous but highly variable; Widespread in brain - partially overlaps that of ENT1 and is similar to that of the A1 type receptor
    • concentrative transporters seem to be restricted to the apical membrane of polarized epithelial cells
  1. SLC 29
    • Equilibrative Nucleoside Transporters - ENT1-4
    • Mediate bidirectional facilitated diffusion, sodium-independent transport
    • hENT1 and hENT2 are well studied
      • lower affinities for natural nucleosides than CNT
      • wide variety of substrates
      • natural targets for vasodilatation potentiators: Dipyramidole, dilazep and draflazine (hENT1 more sensitive than hENT2)
    • ubiquitous transporters, with significant variability in tissue abundance
      • hENT1 - erythrocytes, vascular endothelium, placenta, brain, heart, liver or colon
      • hENT2 - vascular endothelium, heart, brain, placenta, thymus, pancreas, prostate and kidney, with particularly high expression in skeletal muscle
      • hENT3 - widely expressed in human tissues but is particular abundant in placenta
      • hENT4 - especially abundant in the heart, in particular in ventricular myocytes and vascular endothelial cells but is virtually absent from the sino-atrial and atrio-ventricular nodes
    • More likely to be present in the baso-lateral membranes of cells

Pharmacological Relevance of Nucleoside Transporters

  • There is no evidence of NTs being implicated in the pathogenesis of any human disease.
  • Expression of these transporters in cancer cells is necessary for their cytotoxicity as these are a must for transport across cell membranes
  • Distribution of NTs in absortive and secretory organs may determine nucleoside analog pharmacokinetics and toxicological properties
  • Equilibrative nucleoside transporters could serve as drug targets - dipyridamole and dilazep have long been used as vasodilatory drugs

Cardiovascular Drugs

  • Adenosine has important cardiovascular effects and presents a cardioprotective value during ischaemic insult or increased myocardial workload.
  • Cardiac NTs could regulate such responses by modulating extracellular adenosine levels
  • ENT inhibitors dilazep, draflazine and dipyridamole produce a clinically relevant vasodilatory effect in the coronary vasculature, as they restrict adenosine uptake and, thus, enhance extracellular concentrations of the nucleoside.
  • In the presence of coronary atherosclerosis, dipyridamole produces greater increase in flow in normal vessels compared with diseased vessels, because the latter exhibit less vasodilation by adenosine
  • In addition to causing vasodilation, dipyridamole can also inhibit platelet aggregation and proliferation of vascular smooth muscle cells

Anticancer and Antiviral Drugs

  • Several nucleoside-derivatives are currently used in anti- viral and antitumoral therapies.
  • The difference between antitumoral and antiviral drugs is that the latter lack the 3’hydroxyl group of the sugar. Analysis of substrate structural determinants demonstrates that this residue is relevant for nucleoside recognition and translocation, indicating that a slight structural modifications provokes a dramatic change in transportability
  • Studies comparing NT protein profiles with clinical parameters relevant to outcome and survival in solid tumours are still scarce, due to the difficulty to obtain samples and the need of suitable antibodies.
  • The absence of hENT1 protein is associated with reduced survival in gemcitabine-treated patients suffering from pancreatic adenocarcinoma

    Pharmacological Properties of Nucleoside Transporters (Click to Enlarge)
  • Nucleoside transporter expression in human tumours is variable and increasing experimental evidence supports the view that NTs might play a crucial role in nucleoside-derived drug bioavailability and responsiveness.


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