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1 Pharmaceutics, University of Washington, Seattle, Washington, United States
2 Zoology, University of Washington, Seattle, Washington, United States
3 Pathology, University of Washington, United States
4 Seattle, Washington, United States; Pharmaceutics, University of Washington, Seattle, Washington, United States
5 Department of Biochemistry and Molecular Biology, University of Barcelona, Seattle, Washington, Spain
6 Med, GI Div, Johns Hopkins U, Baltimore, Maryland, United States
7 Department of pharmaceutical Sciences, University of Maryland, United States
* To whom correspondence should be addressed. E-mail: jash{at}u.washington.edu.
To better understand the role of human equilibrative (hENTs) and concentrative (hCNTs) nucleoside transporters in physiology and pharmacology, we investigated the regional, cellular and spatial distribution of two hCNTs (hCNT1 and hCNT2) and two hENTs (hENT1 and hENT2) in four human tissues. Using in situ hybridization and immunohistochemical techniques, we found that the duodenum expressed hCNT1 and hCNT2 mRNAs in the enterocytes and hENT1 and hENT2 mRNAs in the crypt cells. In these cells, the hCNT and hENT proteins were predominately localized in the apical and lateral membrane, respectively. Hepatocytes expressed higher levels of mRNAs of hENT1, hCNT1 and hENT2 than of hCNT2 and expressed all these proteins at hepatocyte cell-borders and in the cytoplasm. While the kidney expressed hCNT1 and hCNT2 mRNAs in the proximal tubules, hENT1 and hENT2 mRNAs were present in the distal tubules, glomeruli, endothelial cells and vascular smooth muscle cells. Proximal tubules adjacent to cortico-medullary junctions expressed hENT1, hCNT1 and hCNT2 mRNA. Immunolocalization studies revealed predominant localization of hCNTs in the brush-border membrane of the proximal tubular epithelial cells and hENTs in the basolateral membrane of the distal tubular epithelial cells. Chorionic villi sections of human term placenta expressed mRNAs and proteins for hENT1 and hENT2 but only mRNA for hCNT2. Immunolocalization studies showed presence of hENT1 in the brush-border membrane of the syncytiotrophoblasts. These data are critical for a better understanding of the role of nucleoside transporters in the physiological and pharmacological effects of nucleosides and nucleoside drugs respectively.
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