Nucleoside and nucleobase transport systems of mammalian cells

Griffith, Douglas A.; Jarvis, Simon M.

doi:10.1016/s0304-4157(96)00008-1

Cited by 460 publications

(470 citation statements)

References 273 publications

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“…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. 1E and F).…”

Section: Rbv R Huh75 Cells With Reduced Rbv Uptakementioning

confidence: 81%

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: 81%

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

Ibarra

Jain

Pfeiffer

2011

J Virol

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“…Whether or not specific corneal uptake mechanisms subserve the more rapid penetration of adenosine and MRS 1191 is unclear. For example, both sodium-dependent and the sodium-independent, equilibrative nucleoside salvage pathways have been described in other mammalian cells (Griffith DA and Jarvis, 1996;Cass et al, 1998), and an N3 sodiumdependent nucleoside salvage pathway has been reported in rabbit cornea (Majumdar et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Barrier qualities of the mouse eye to topically applied drugs

Wang

Wai

Ávila

et al. 2007

Experimental Eye Research

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The mouse eye displays unusually rapid intraocular pressure (IOP) responses to topically applied drugs as measured by the invasive servo-null micropipette system (SNMS). To learn if the time course reflected rapid drug transfer across the thin mouse cornea and sclera, we monitored a different parameter, pupillary size, following topical application of droplets containing 40 μM (0.073μg) carbachol. No miosis developed from this low carbachol concentration unless the cornea was impaled with an exploring micropipette as used in the SNMS. We also compared the mouse IOP response to several purinergic drugs, measured by the invasive SNMS and non-invasive pneumotonometry. Responses to the previously-studied non-selective adenosine-receptor (AR) agonist adenosine, the A 3 -selective agonist Cl-IB-MECA and the A 3 -selective antagonist MRS 1191 were all enhanced to varying degrees, in time and magnitude, by corneal impalement.We conclude that the thin ocular coats of the mouse eye actually present a substantial barrier to drug penetration. Corneal impalement with even fine-tipped micropipettes can significantly enhance entry of topically-applied drugs into the mouse aqueous humor, reflecting either direct diffusion around the tip or a more complex impalement-triggered change in ocular barrier properties. Comparison of invasive and non-invasive measurement methods can document drug efficacy at intraocular target sites even if topical drug penetration is too slow to manifest convincing physiologic effects in intact eyes.

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“…Some animal cells, including intestinal enterocytes, bone marrow, certain brain cells, erythrocytes, and leukocytes, are unable to synthesize purines de novo and thus must take up purines de- rived from dietary sources or from de novo synthesis by other cells, especially hepatocytes (26). It is now recognized that there are multiple carriers for the transport of nucleosides and nucleobases that function either by facilitated diffusion or Na + -cotransport (2,26,27). Thorell et al (18), using homogenates of fetal small intestine and human milk with and without added RNA, found CMP, UMP, and adenosine monophosphate, cytidine and uridine, hypoxhantine, xanthine, and uric acid after 4 hours of incubation.…”

Section: Discussionmentioning

confidence: 99%

Ribonucleic Acid Hydrolysis by Intestinal Explants of Neonatal Piglets

Rueda¹,

Gómez-León²,

Gil³

2002

Journal of Pediatric Gastroenterology and Nutrition

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Background: Healthy human adults are able to hydrolyze dietary nucleic acids and nucleotides in the gastrointestinal tract, thus facilitating absorption of the resulting nucleosides. However, little is directly known of the ability of infants to hydrolyze nucleic acids early in life. Methods: Purified RNA (50, 100, 250, and 500 mg/L) in a suitable medium was exposed to jejunal explants of weaning piglets to determine if enzymes expressed by the explants were sufficient to hydrolyze the nucleic acid. Aliquots from the media were taken at time intervals, from 0 to 6 hours, and assayed for ribonucleoside content by high-performance liquid chromatography. Results: The investigators found a significant increase of free ribonucleosides during the study period and for all RNA concentrations tested, thus suggesting that intestinal explants are able to hydrolyze RNA. The kinetics of nucleoside concentrations varied for each nucleoside. For example, inosine increased over the entire 6-hour period and adenosine increased for the first 2 hours, decreasing afterward. Conclusions: It is concluded that cells from the intestinal epithelium are capable of hydrolyzing RNA. These results suggest that RNA present in human milk is hydrolyzed in the intestinal tract of the breast-fed infant, thus providing an additional source of nucleosides. The results indicate that current supplementation of infant formulas with nucleotides should be reconsidered to take into account the contribution of RNA present in human milk to the pool of bioavailable nucleotides. JPGN 35:685-690, 2002.

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Nucleoside and nucleobase transport systems of mammalian cells

Cited by 460 publications

References 273 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

Barrier qualities of the mouse eye to topically applied drugs

Ribonucleic Acid Hydrolysis by Intestinal Explants of Neonatal Piglets

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