NUCLEOSIDE TRANSPORTERS: CNTs AND ENTs - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 190

identified for hCNT2, hCNT3, hENT1, and hENT2, suggesting that coding region
SNPs of these transporters are unlikely to contribute to interindividual differences
in response to nucleoside analog drugs. 42 , 140-142 Recently, Myers et al. examined
1.6 kb upstream of the transcription initiation site of hENT1 in a limited DNA sample
collection. 143

C) were
found, and analysis of four naturally occurring haplotypes suggests that promoter re-
gion haplotypes may affect hENT1 gene expression. 143 The regulatory-region SNPs
might offer additional clues to the considerable variability in nucleoside transporter
abundance observed in normal and tumor tissues.

Three SNPs ( − 1345C > G, − 1050G > A, and − 706G >

8.8. CONCLUSIONS

In recent years, significant progress has been made in the studies of nucleoside trans-
porters. Molecular cloning of the CNT and ENT genes has promoted studies that
have greatly enhanced our understanding of the substrate and inhibitor specifici-
ties, tissue and cellular localization, structure-function relationships, and regulation
mechanisms of nucleoside transporters. Knowledge obtained from these studies will
pave the way for rational design and development of nucleoside analog drugs with
improved pharmacokinetic and pharmacodynamic properties. The first nucleoside
transporter-deficient animal has recently been generated for ENT1. 128 Detailed phe-
notyping and pharmacological analysis in nucleoside-transporter knockout animal
models will provide insights into the physiological, pharmacological, and toxicologi-
cal functions of nucleoside transporters in vivo, in the context of complex intracellular
metabolism and the presence of other transporters (e.g., OATs, MRPs) that also trans-
port some nucleoside analogs and/or their active metabolites. Recently, studies have
been launched to correlate nucleoside transporter expression levels with clinical out-
comes of therapeutic nucleosides. Pharmacogenomic studies have been undertaken to
elucidate the mechanisms leading to inter-individual variations in response to nucleo-
side drugs. Knowledge gained from these studies will undoubtedly benefit the design,
development, and clinical optimization of new and existing nucleoside analogs.

Acknowledgments

This work is supported by NIH grant GM66233.

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