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.

Biochemistry and Cell Biology - Tập 84 Số 6 - Trang 844-858 - 2006
Adam Elwi1,2,3,4, Vijaya L. Damaraju1,2,3,4, Stephen A. Baldwin1,2,3,4, James D. Young1,2,3,4, Michael B. Sawyer1,2,3,4, Carol E. Cass1,2,3,4
1Astbury Centre for Structural Molecular Biology, Institute for Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK.
2Department of Oncology and the Membrane Protein Research Group, University of Alberta, Edmonton, Alta., Canada, and Department of Experimental Oncology, Cross Cancer Institute, Edmonton, Alta., Canada.
3Department of Oncology, University of Alberta, Edmonton, Alta., Canada, and Department of Medical Oncology, Cross Cancer Institute, Edmonton, Alta., Canada.
4Department of Physiology and the Membrane Research Group, University of Alberta, Edmonton, Alta., Canada.

Tóm tắt

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.

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Biochemistry and Cell Biology

Tập 84 Số 6

844-858

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