Elwi Adam N, Damaraju Vijaya L, Baldwin Stephen A, Young James D, Sawyer Michael B, Cass Carol E
Department of Oncology and the Membrane Protein Research Group, University of Alberta, Edmonton, Alta., Canada.
Biochem Cell Biol. 2006 Dec;84(6):844-58. doi: 10.1139/o06-198.
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.
肾脏对生理性和药理学核苷的处理是其血浆水平和组织可用性的主要决定因素。此外，核苷药物的药代动力学和正常组织毒性受其在肾脏中的处理方式影响。核苷的肾脏重吸收或分泌具有选择性，且依赖于存在于肾上皮中的整合膜蛋白，即核苷转运体（NTs）。已知的7种人类NTs（hNTs）表现出不同的通透选择性，分为2个蛋白家族：溶质载体（SLC）29（SLC29A1、SLC29A2、SLC29A3、SLC29A4）和SLC28（SLC28A1、SLC28A2、SLC28A3）蛋白，分别也被称为人类平衡核苷转运体（hENTs，hENT1、hENT2、hENT3、hENT4）和人类浓缩核苷转运体（hCNTs，hCNT1、hCNT2、hCNT3）。特征明确的hENTs（hENT1和hENT2）是质膜中的双向易化扩散转运体；hENT3和hENT4的了解较少，尽管在溶酶体膜中发现的hENT3转运核苷且依赖于pH，而hENT4-PMAT是一种H⁺-腺苷共转运体以及单胺-有机阳离子转运体。3种hCNTs是单向继发性主动Na⁺-核苷共转运体。在肾上皮细胞中，顶端膜上的hCNT
