Renal nucleoside transporters: physiological and clinical implicationsThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 844-858 ◽  
Author(s):  
Adam N. Elwi ◽  
Vijaya L. Damaraju ◽  
Stephen A. Baldwin ◽  
James D. Young ◽  
Michael B. Sawyer ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Membrane Proteins ◽  
Organic Cation ◽  
Nucleoside Transporters ◽  
Nucleoside Transport ◽  
Multidrug Resistance Proteins ◽  
Renal Epithelia ◽  
Renal Handling ◽  
Basolateral Membranes ◽  
Nucleoside Drugs

Renal handling of physiological and pharmacological nucleosides is a major determinant of their plasma levels and tissue availabilities. Additionally, the pharmacokinetics and normal tissue toxicities of nucleoside drugs are influenced by their handling in the kidney. Renal reabsorption or secretion of nucleosides is selective and dependent on integral membrane proteins, termed nucleoside transporters (NTs) present in renal epithelia. The 7 known human NTs (hNTs) exhibit varying permeant selectivities and are divided into 2 protein families: the solute carrier (SLC) 29 (SLC29A1, SLC29A2, SLC29A3, SLC29A4) and SLC28 (SLC28A1, SLC28A2, SLC28A3) proteins, otherwise known, respectively, as the human equilibrative NTs (hENTs, hENT1, hENT2, hENT3, hENT4) and human concentrative NTs (hCNTs, hCNT1, hCNT2, hCNT3). The well characterized hENTs (hENT1 and hENT2) are bidirectional facilitative diffusion transporters in plasma membranes; hENT3 and hENT4 are much less well known, although hENT3, found in lysosomal membranes, transports nucleosides and is pH dependent, whereas hENT4–PMAT is a H+-adenosine cotransporter as well as a monoamine–organic cation transporter. The 3 hCNTs are unidirectional secondary active Na+-nucleoside cotransporters. In renal epithelial cells, hCNT1, hCNT2, and hCNT3 at apical membranes, and hENT1 and hENT2 at basolateral membranes, apparently work in concert to mediate reabsorption of nucleosides from lumen to blood, driven by Na+ gradients. Secretion of some physiological nucleosides, therapeutic nucleoside analog drugs, and nucleotide metabolites of therapeutic nucleoside and nucleobase drugs likely occurs through various xenobiotic transporters in renal epithelia, including organic cation transporters, organic anion transporters, multidrug resistance related proteins, and multidrug resistance proteins. Mounting evidence suggests that hENT1 may have a presence at both apical and basolateral membranes of renal epithelia, and thus may participate in both selective secretory and reabsorptive fluxes of nucleosides. In this review, the renal handling of nucleosides is examined with respect to physiological and clinical implications for the regulation of human kidney NTs and adenosine signaling, intracellular nucleoside transport, and nephrotoxicities associated with some nucleoside drugs.

Localization of broadly selective equilibrative and concentrative nucleoside transporters, hENT1 and hCNT3, in human kidney

2007 ◽  
Vol 293 (1) ◽  
pp. F200-F211 ◽  
Author(s):  
Vijaya L. Damaraju ◽  
Adam N. Elwi ◽  
Charlene Hunter ◽  
Pat Carpenter ◽  
Cheryl Santos ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Membrane Vesicles ◽  
Human Kidney ◽  
Nucleoside Transporters ◽  
Proximal Tubules ◽  
Renal Handling ◽  
Cytoplasmic Staining ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Nucleoside Drugs

Nucleoside transporters in kidney mediate renal reabsorption and secretion of nucleosides. Using RT-PCR, we demonstrated mRNAs encoding hENT1, hENT2, hCNT1, hCNT2, and hCNT3 in both cortex and medulla. Immunoblotting with crude membrane preparations revealed abundant hENT1 and hCNT3 in both cortex and medulla, and little, if any, hENT2, hCNT1, or hCNT2, indicating that the latter were either absent or below limits of detection of immunoassays. hENT1 immunostaining was observed on apical surfaces of proximal tubules and on both apical and basal surfaces of thick ascending loops of Henle and collecting ducts. Prominent hCNT3 immunostaining was observed on apical surfaces of proximal tubules and thick ascending loops of Henle in addition to some cytoplasmic staining. Equilibrium binding of [3H]nitrobenzylmercaptopurine ribonucleoside (NBMPR), a high-affinity inhibitor of hENT1, to brush-border membrane vesicles from cortex confirmed the presence of hENT1 on apical surfaces of proximal tubules. Uptake of [3H]uridine by polarized renal proximal tubule cells exhibited a sodium-dependent component that was inhibited by thymidine and inosine as well as a sodium-independent component that was partially inhibited by NBMPR and completely inhibited by dilazep, indicating high levels of hENT1 and hCNT3 and low levels of hENT2 activities. The presence of 1) transcripts for hENT1/2 and hCNT1/2/3 and the hENT1 and hCNT3 proteins in human kidneys and 2) hENT1, hENT2, and hCNT3 activities in cultured proximal tubule cells suggest involvement of hENT1, hCNT3, and possibly also hENT2 in renal handling of nucleosides and nucleoside drugs.

scholarly journals Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Qingquan Zeng ◽  
Mengru Bai ◽  
Cui Li ◽  
Shuanghui Lu ◽  
Zhiyuan Ma ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Organic Cation ◽  
Antiviral Drug ◽  
Nucleoside Transporters ◽  
Multiple Drug ◽  
Cancer Resistance ◽  
Maternal Circulation ◽  
Human Trophoblast ◽  
Bewo Cells ◽  
Resistance Protein

ABSTRACT Emtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were involved. FTC accumulation in BeWo cells was reduced markedly by inhibitors of equilibrative nucleoside transporters (ENTs), concentrative nucleoside transporters (CNTs), organic cation transporters (OCTs), and organic cation/carnitine transporter 1 (OCTN1) and increased by inhibitors of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs). ENT1, CNT1, OCTN1, MRP1/2/3, and BCRP, but not ENT2, CNT3, OCTN2, or multidrug resistance protein 1 (MDR1), were found to transport FTC. FTC accumulation in PHTCs was decreased significantly by inhibitors of ENTs and OCTN1. These results suggest that ENT1, CNT1, and OCTN1 probably contribute to FTC uptake from maternal circulation to trophoblasts and that ENT1, CNT1, and MRP1 are likely involved in FTC transport between trophoblasts and fetal blood, whereas BCRP and MRP1/2/3 facilitate FTC transport from trophoblasts to maternal circulation. Coexistence of tenofovir or efavirenz with FTC in the cell medium did not influence FTC accumulation in BeWo cells or PHTCs.

Molecular biology and regulation of nucleoside and nucleobase transporter proteins in eukaryotes and prokaryotes

2002 ◽  
Vol 80 (5) ◽  
pp. 623-638 ◽  
Author(s):  
Miguel A Cabrita ◽  
Stephen A Baldwin ◽  
James D Young ◽  
Carol E Cass
Keyword(s):  
Molecular Biology ◽  
Vital Role ◽  
Nucleoside Transporters ◽  
Nucleoside Transport ◽  
Nucleoside Transporter ◽  
Concentration Gradients ◽  
Transporter Proteins ◽  
Equilibrative Nucleoside Transporters ◽  
Nucleoside Drugs ◽  
Nucleobase Transport

The molecular cloning of cDNAs encoding nucleoside transporter proteins has greatly advanced understanding of how nucleoside permeants are translocated across cell membranes. The nucleoside transporter proteins identified thus far have been categorized into five distinct superfamilies. Two of these superfamilies, the equilibrative and concentrative nucleoside transporters, have human members and these will be examined in depth in this review. The human equilibrative nucleoside transporters translocate nucleosides and nucleobases bidirectionally down their concentration gradients and are important in the uptake of anticancer and antiviral nucleoside drugs. The human concentrative nucleoside transporters cotranslocate nucleosides and sodium unidirectionally against the nucleoside concentration gradients and play a vital role in certain tissues. The regulation of nucleoside and nucleobase transporters is being studied more intensely now that more tools are available. This review provides an overview of recent advances in the molecular biology and regulation of the nucleoside and nucleobase transporters.Key words: nucleoside transporter, nucleoside transport, nucleobase transporter, nucleobase transport, regulation of nucleoside and nucleobase transport, nucleoside drugs.

Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia

2001 ◽  
Vol 120 (5) ◽  
pp. A93-A93
Author(s):  
D ROST ◽  
J KONIG ◽  
G WEISS ◽  
E KLAR ◽  
W STREMMEL ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Multidrug Resistance Proteins ◽  
Human Gallbladder ◽  
Resistance Proteins

Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3)

2006 ◽  
Vol 159 (3) ◽  
pp. 169-179 ◽  
Author(s):  
Anne Lespine ◽  
Jacques Dupuy ◽  
Stéphane Orlowski ◽  
Tünde Nagy ◽  
Hristos Glavinas ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Multidrug Resistance Proteins ◽  
Resistance Proteins

scholarly journals The Emerging Role of Extracellular Vesicle-Mediated Drug Resistance in Cancers: Implications in Advanced Prostate Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Carolina Soekmadji ◽  
Colleen C. Nelson
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Advanced Prostate Cancer ◽  
Control Cell ◽  
Extracellular Vesicle ◽  
Multidrug Resistance Proteins ◽  
Acquired Drug Resistance ◽  
Resistance Proteins

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

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