Transporters nucleoside

Nucleoside analogues are widely used for the treatment of cancers and viral infections. Although there have been considerable advances in the development of new nucleoside analogs, little is known about the transport mechanisms involved in the intestinal absorption of these compounds. Nucleoside transporters have been subdivided into two major classes by Na+-independent equilibrative transporters (ENT family) and Na+-dependent concentrative transporters (CNT family) [77,100-103], 

Concentrative nudeoside CNT1 azidothymidine(AZT), zaldtabine, dadribine, 

Equilibrative nudeoside ENT1 dadribine, cytarabine, fludarabine, 

The lack of high-affinity inhibitors and, for a long time, suitable antibodies has 

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Nimodipine, but not other DHPs, is also a potent inhibitor of nucleoside transport with actions similar to known nucleoside transport inhibitors such as dipyr-idamol. It is likely that this mechanism also contributes to the potent vasodilating properties of this DHP. 

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

Aymerich I, Duflot S, Fernandez-Veledo S, Guillen-Gomez E, Huber-Ruano I, Casado FJ, et al. The concentrative nucleoside transporter family (SLC28) new roles beyond salvage Biochem Soc Trans 2005 33 216-9. 

Viswanadhan VN, Ghose AK and Weinstein JN. Mapping the binding site of the nucleoside transporter protein a 3D-OSAR study. Biochim Biophys Acta 1990 1039 356-66. 

Chang C, Swaan PW, Ngo LY, Lum PY, Patil SD and Unadkat JD. Molecular requirements of the human nucleoside transporters hCNTl, hCNT2, and hENTl. Mol Pharmacol 2004 65 558-70. 

K Hosoya, Y Horibe, KJ Kim, VHL Lee. (1998). Nucleoside transport mechanisms in the pigmented rabbit conjunctiva. Invest Ophthalmol Vis Sci 39 372-377. 

Figure 12.2 Adenosine metabolism. Intracellular adenosine concentrations depend on the balance between energy storage and breakdown. The most important enzymes catalyzing the reactions are indicated. SAH, S-adenosyl-homocysteine ENTs equilibrative nucleoside transporters CNTs, concentrating nucleoside transporters.

Adenosine metabolism (Fig. 12.2) is reviewed in Dunwiddie Masino (2001) and Ribeiro et al. (2002). The phosphorylation of intracellular adenosine to AMP is catalyzed by adenosine kinase. Intracellularly, adenosine can also be deami-nated to inosine by adenosine deaminase. Free intracellular adenosine is normally low. Excess adenosine, which cannot be regenerated to ATP, is extruded to the extracellular space by equilibrative nucleoside transporters (ENTs) in the cell membrane. During electrical stimulation or energy depletion, adenosine is... 

Increasing extracellular adenosine levels by blocking the nucleoside transporter system has been suggested to improve sleep. The nucleoside transport... 

Alanko, L Stenberg, D. Porkka-Heiskanen, T. (2003b). Nitrobenzylthioinosine (NBMPR) binding and nucleoside transporter ENT1 mRNA expression after prolonged wakefulness and recovery sleep in the cortex and basal forebrain of rat. J. Sleep Res. 12 (4), 299-304. 

Anticonvulsant action of the nucleoside transport inhibitor, soluflazine, on synaptic and non-synaptic epileptogenesis in the guinea-pig hippocampus. Epilepsy Res. 2 (2), 65-71. 

Hoppenbrouwers, M. L. Van den Busche, G. (1987). Mioflazine, a nucleoside transport inhibitor effective as sleep promotor in humans . Abstract, International Symposium Current Trends in Slow Wave Sleep Research, Beerse, Belgium, p. 38. 

Wauquier, A., Van Belle, H., Van den Broeck, W. A. Janssen, P. A. (1987). Sleep improvement in dogs after oral administration of mioflazine, a nucleoside transport inhibitor. Psychopharmacology 91 (4), 434-9. 

Yao, S. Y., Ng, A. M., Muzyka, W. R. et al. (1997). Molecular cloning and functional characterization of nitrobenzylthioinosine (NBMPR)-sensitive (es) and NBMPR-insensitive (ei) equilibrative nucleoside transporter proteins (rENTl and rENT2) from rat tissues. /. Biol. Chem. 272 (45), 28423-30. 

Fig.n.2. Human duodenal expression variability of nucleoside, organic cation ion, and anion transporters (unpublished data). Shaded box indicates 25-75% of expression range, the line within the box marks the median, and error bars indicate 10-90% of expression range. ENT2, equilibrative nucleoside transporter CNT1, concentrative pyrimidine nucleoside transporter CNT2, concentrative purine nucleoside transporter ... 

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