Striking Species Difference in the Contribution of Concentrative Nucleoside Transporter 2 to Nucleoside Uptake between Mouse and Rat Hepatocytes

Furihata, Tomomi; Fukuchi, Yukina; Iikura, Minami; Hashizume, Misato; Miyajima, Atsushi; Nagai, Miki; Chiba, Kazuhiro

doi:10.1128/aac.00010-10

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…Such data are comparatively unavailable in the academic literature, and we strongly encourage their publication so that people can see the extent of the inter-species variation of drug uptake into particular organs or tissues, which variation can again be considerable (e.g., Shilling et al, 2006 ; Shitara et al, 2006 ; Li et al, 2008 ; Furihata et al, 2010 ; Chu et al, 2013a ; Grime and Paine, 2013 ; Musther et al, 2014 ).…”

Section: We Propose Some Candidate Discriminating Experiments That Admentioning

confidence: 99%

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Kell¹,

Oliver²

2014

Front. Pharmacol.

146

169

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One approach to experimental science involves creating hypotheses, then testing them by varying one or more independent variables, and assessing the effects of this variation on the processes of interest. We use this strategy to compare the intellectual status and available evidence for two models or views of mechanisms of transmembrane drug transport into intact biological cells. One (BDII) asserts that lipoidal phospholipid Bilayer Diffusion Is Important, while a second (PBIN) proposes that in normal intact cells Phospholipid Bilayer diffusion Is Negligible (i.e., may be neglected quantitatively), because evolution selected against it, and with transmembrane drug transport being effected by genetically encoded proteinaceous carriers or pores, whose “natural” biological roles, and substrates are based in intermediary metabolism. Despite a recent review elsewhere, we can find no evidence able to support BDII as we can find no experiments in intact cells in which phospholipid bilayer diffusion was either varied independently or measured directly (although there are many papers where it was inferred by seeing a covariation of other dependent variables). By contrast, we find an abundance of evidence showing cases in which changes in the activities of named and genetically identified transporters led to measurable changes in the rate or extent of drug uptake. PBIN also has considerable predictive power, and accounts readily for the large differences in drug uptake between tissues, cells and species, in accounting for the metabolite-likeness of marketed drugs, in pharmacogenomics, and in providing a straightforward explanation for the late-stage appearance of toxicity and of lack of efficacy during drug discovery programmes despite macroscopically adequate pharmacokinetics. Consequently, the view that Phospholipid Bilayer diffusion Is Negligible (PBIN) provides a starting hypothesis for assessing cellular drug uptake that is much better supported by the available evidence, and is both more productive and more predictive.

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Section: We Propose Some Candidate Discriminating Experiments That Admentioning

confidence: 99%

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Kell¹,

Oliver²

2014

Front. Pharmacol.

146

169

View full text Add to dashboard Cite

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“…However, whether and how the increase of CD157 involved in the function of cardiac Tregs post MI need further exploration. CNT2, a high-affinity adenosine transporter mediating salvage of nucleoside, modulation of purinergic signaling, and energy metabolism in intestinal and liver parenchymal cells, also exhibited a marked elevation in cardiac Tregs at day 7 post-MI 39 - 41 . Borg et al reported no difference in Cnt2 expression in CD4 + T-cells from blood and heart 3 days after I/R injury 23 , but our results suggested that CNT2 may also exert its function in injured hearts by regulating purinergic signaling on T cells post-MI.…”

Section: Discussionmentioning

confidence: 99%

CD4⁺FoxP3⁺CD73⁺ regulatory T cell promotes cardiac healing post-myocardial infarction

Zhuang¹,

Meng²,

Ma³

et al. 2022

Theranostics

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Rationale: Despite recent studies indicating a crucial role of ecto-5′-nucleotidase (CD73) on T cells in cardiac injury after ischemia/reperfusion, the involvement of CD73 + regulatory T cells (Tregs) in cardiac repair post-myocardial infarction (MI) remains unclear. We sought to investigate the contribution of CD73 on Tregs to the resolution of cardiac inflammation and remodeling after MI. Methods: Cardiac function, tissue injury, Tregs percentage in injured hearts, and purinergic signaling changes in cardiac FoxP3 + Tregs were analyzed after permanent descending coronary artery ligation. CD73 knockout Tregs were used to determine the function of CD73 on Tregs. Peripheral blood mononuclear cells (PBMCs) from acute myocardial infarction (AMI) patients and matched non-MI subjects were assessed via flow cytometry. Results: Cardiac Tregs exhibited distinction of purinergic signaling post MI with dramatically high level of CD73 compared to the sham Tregs. CD73 deficiency decreased the tissue tropism, and impaired the immunosuppressive and protective function of Tregs in cardiac healing. Administration of low-dose of IL-2/anti-IL-2 complex resulted in FoxP3 + CD73 + Tregs expansion in the heart and contributed to the recovery of cardiac function. CD73 derived from FoxP3 + Tregs could bind to FoxP3 - effector T-cells and inhibit the production of multiple inflammatory cytokines. In AMI patients, CD73 expressions on both CD4 + cells and FoxP3 + Tregs decreased in PBMCs. Moreover, CD73 expressions on CD4 + T cells were negatively correlated with the levels of NT pro-BNP and myocardial zymogram in serum. Conclusions: Our findings indicated the importance of FoxP3 + CD73 + Tregs in inflammation resolution and cardiac healing post-MI.

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“…Uridine is also a substrate for ENT3, but the intracellular location of this transporter discards any role in initial cellular uptake of uridine [12], whereas ENT4 fails to transport uridine [9]. To discriminate among CNT and ENT activities, we used the differential sensitivity of these transporters to sodium withdrawal and to inhibitors such as NBMPR (which inhibits ENT1 when used at 100 nM and ENT1 and ENT2 when used at 100 µM, but not CNTs) [30], thymidine (blocking CNT1 and CNT3) [19] and inosine (blocking CNT2 and CNT3) [31] (Table 1).…”

Section: Methodsmentioning

confidence: 99%

mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

et al. 2018

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The HepaRG cell line is a highly differentiated human hepatoma cell line, displaying the expression of various drug transporters. However, functional expression of nucleoside transporters remains poorly characterized in HepaRG cells, although these transporters play a key role in hepatic uptake of antiviral and anticancer drugs. The present study was, therefore, designed to characterize the expression, activity and regulation of equilibrative (ENT) and concentrative (CNT) nucleoside transporter isoforms in differentiated HepaRG cells. These cells were found to exhibit a profile of nucleoside transporter mRNAs similar to that found in human hepatocytes, i.e., notable expression of ENT1, ENT2 and CNT1, with very low or no expression of CNT2 and CNT3. ENT1 activity was, next, demonstrated to be the main uridine transport activity present in HepaRG cells, like in cultured human hepatocytes. Various physiological factors, such as protein kinase C (PKC) activation or treatment by inflammatory cytokines or hepatocyte growth factor (HGF), were additionally found to regulate expression of ENT1, ENT2 and CNT1; PKC activation and HGF notably concomitantly induced mRNA expression and activity of ENT1 in HepaRG cells. Overall, these data suggest that HepaRG cells may be useful for analyzing cellular pharmacokinetics of nucleoside-like drugs in human hepatic cells, especially of those handled by ENT1.

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Striking Species Difference in the Contribution of Concentrative Nucleoside Transporter 2 to Nucleoside Uptake between Mouse and Rat Hepatocytes

Cited by 6 publications

References 10 publications

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

CD4⁺FoxP3⁺CD73⁺ regulatory T cell promotes cardiac healing post-myocardial infarction

mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

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Striking Species Difference in the Contribution of Concentrative Nucleoside Transporter 2 to Nucleoside Uptake between Mouse and Rat Hepatocytes

Cited by 6 publications

References 10 publications

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

CD4+FoxP3+CD73+ regulatory T cell promotes cardiac healing post-myocardial infarction

mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

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CD4⁺FoxP3⁺CD73⁺ regulatory T cell promotes cardiac healing post-myocardial infarction