Human intestinal es nucleoside transporter: molecular characterization and nucleoside inhibitory profiles

Lum, Pek Yee; Ngo, Leock Y.; Bakken, Aimée H.; Unadkat, Jashvant D.

doi:10.1007/s002800050040

Cited by 25 publications

(34 citation statements)

References 13 publications

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“…1D). No significant reduction in RBV uptake was observed with a higher concentration of NBMPR (100 M), which inhibits both ENT1 and ENT2 (34,52). While the literature indicates that NBMPR treatment specifically inhibits ENT-mediated transport, we cannot exclude the remote possibility that another NBMPR-sensitive RBV transporter exists (34,52).…”

Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 58%

“…9). Treatment with 100 M NBMPR, which inhibits ENT1 and ENT2 (34,52), yielded similar results. Therefore, ENT1 is a major RBV transporter in primary human PBMCs.…”

mentioning

confidence: 56%

“…No significant reduction in RBV uptake was observed with a higher concentration of NBMPR (100 M), which inhibits both ENT1 and ENT2 (34,52). While the literature indicates that NBMPR treatment specifically inhibits ENT-mediated transport, we cannot exclude the remote possibility that another NBMPR-sensitive RBV transporter exists (34,52). Inhibition of concentrative transport through phloridzin treatment, an inhibitor of sodium-dependent nucleoside transport (25,47), did not reduce RBV uptake in cells, unless they expressed CNT3 via transfection ( Fig.…”

Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 99%

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Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Ibarra

Jain

Pfeiffer

2011

J Virol

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Many individuals infected with hepatitis C virus (HCV) develop a chronic infection, and of those who are treated with pegylated interferon and ribavirin (RBV), many do not respond. While the nucleoside analog RBV improves treatment outcome, and will likely be an important component of therapy with next-generation viral inhibitors, RBV's mechanism is controversial. Most of RBV's proposed mechanisms require RBV import into cells. Therefore, we explored whether host-based RBV resistance develops through reduced cellular uptake, akin to chemotherapy resistance in some cancers. We examined the effect of host-based RBV resistance on HCV replication in cultured hepatoma Huh7.5 liver cells and whether RBV resistance develops in HCV patients. When Huh7.5 cells were exposed to RBV, resistance developed through reduced RBV uptake via the ENT1 nucleoside transporter and antiviral efficacy was reduced. The uptake defect in RBV-resistant cells was specific to RBV, since transport of another ENT1 substrate, cytidine, was unaffected. Importantly, RBV uptake significantly declined in HCV patient peripheral blood mononuclear cells (PBMCs) following 4 weeks of therapy. Furthermore, maintenance of RBV uptake correlated with rapid treatment response. Our results uncovered a novel form of antiviral drug resistance and suggest that host-based RBV resistance develops in HCV patients undergoing therapy and that maintenance of RBV uptake may contribute to rapid viral clearance.

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Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 58%

“…9). Treatment with 100 M NBMPR, which inhibits ENT1 and ENT2 (34,52), yielded similar results. Therefore, ENT1 is a major RBV transporter in primary human PBMCs.…”

mentioning

confidence: 56%

Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 99%

See 1 more Smart Citation

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Ibarra

Jain

Pfeiffer

2011

J Virol

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“…The high abundance of CNTs in liver and renal tissues may contribute to the renal and hepatic toxicities observed when patients are treated with nucleoside analog drugs (Loewen et al, 1999). In the intestine, CNTs were localized by functional studies to brush border membranes (Chandrasena et al, 1997;Patil and Unadkat, 1997;Ngo et al, 2001), whereas ENTs were localized to basolateral membranes (Chandrasena et al, 1997;Lum et al, 2000). There is a wide variation in the expression of hCNT1 mRNA in normal kidney in different individuals (Pennycooke et al, 2001) and relatively low levels of expression of hCNT1 mRNA in tumor samples (Pennycooke et al, 2001).…”

Section: Chromosomal Localization Of Transporter Genesmentioning

confidence: 99%

Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy

et al. 2003

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The clinical efficacy of anticancer nucleoside drugs depends on a complex interplay of transporters mediating entry of nucleoside drugs into cells, efflux mechanisms that remove drugs from intracellular compartments and cellular metabolism to active metabolites. Nucleoside transporters (NTs) are important determinants for salvage of preformed nucleosides and mediated uptake of antimetabolite nucleoside drugs into target cells. The focus of this review is the two families of human nucleoside transporters (hENTs, hCNTs) and their role in transport of cytotoxic chemotherapeutic nucleoside drugs. Resistance to anticancer nucleoside drugs is a major clinical problem in which NTs have been implicated. Single nucleotide polymorphisms (SNPs) in drug transporters may contribute to interindividual variation in response to nucleoside drugs. In this review, we give an overview of the functional and molecular characteristics of human NTs and their potential role in resistance to nucleoside drugs and discuss the potential use of genetic polymorphism analyses for NTs to address drug resistance.

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“…Because hCNT1, hCNT2, and hENT1 are expressed in tissues important for drug disposition, in the current study we have generated distinctive pharmacophore models for each of these nucleoside transporters using the distance comparisons technique (Martin et al, 1993). We used inhibition profiles of hCNT2, hCNT1, and hENT1 transporters from our laboratory (Lum et al, 2000;Patil et al, 2000) to gain insight into the different binding mechanisms and requirements of these three nucleoside transporters. Subsequently, to generate 3D-QSARs, we performed comparative molecular field analysis (CoMFA) (Cramer et al, 1988), which provides subtle and unique structure-activity correlations for each individual nucleoside transporter.…”

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confidence: 99%

Molecular Requirements of the Human Nucleoside Transporters hCNT1, hCNT2, and hENT1

et al. 2004

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Concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs) are important in physiological and pharmacological activity and disposition of nucleosides and nucleoside drugs. A better understanding of the structural requirements of inhibitors for these transporters will aid in designing therapeutic agents. To define the relative and unified structural requirements of nucleoside analogs for interaction with hCNT1, hCNT2, and hENT1, we applied an array of structure-activity techniques. Unique pharmacophore models for each respective nucleoside transporter were generated. These models reveal that hCNT2 affinity is dominated by hydrogen bonding features, whereas hCNT1 and hENT1 displayed mainly electrostatic and steric features. Hydrogen bond formation over 3Ј-OH is essential for all nucleoside transporters. Inhibition of nucleoside transporters by a series of uridine and adenosine analogs and a variety of drugs was analyzed by comparative molecular field analysis. Cross-validated r 2 (q 2 ) values were 0.65, 0.52, and 0.74 for hCNT1, hCNT2, and hENT1, respectively. The predictive quality of the models was further validated by successful prediction of the inhibition of a set of test compounds. Addition of a hydroxyl group around the 2-position of purine (or 3-position of pyrimidine) may increase inhibition to hCNT2 transporter; addition of hydroxyl group around the 2,7-position of purine (or the 3,5-position of pyrimidine) would increase the inhibition to hENT1 transporter. Utilization of these models should assist the design of high-affinity nucleoside transporter inhibitors and substrates for both anticancer and antiviral therapy.

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Human intestinal es nucleoside transporter: molecular characterization and nucleoside inhibitory profiles

Cited by 25 publications

References 13 publications

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy

Molecular Requirements of the Human Nucleoside Transporters hCNT1, hCNT2, and hENT1

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