Human nucleoside transporters are encoded by SLC28 (hCNTs) and SLC29 (hENTs) genes. These proteins mediate the uptake of anticancer and some antiviral drugs and are also suitable candidates to facilitate nucleoside-derived drug uptake into hepatocytes for detoxification. Despite the putative relevance of these genes in liver physiology, the human SLC28 and SLC29 expression pattern is not known and suitable cell models are not available. These issues have been addressed by examining NT expression in human liver and primary cultures of human hepatocytes. Moreover, the effect of specific liver enriched transcription factors (LETFs) in hCNTs expression has been analyzed. Human hepatocytes express hCNT1, hCNT2, hENT1, and hENT2. Loss of the hepatic phenotype in primary culture is associated with a decrease in hCNT1 and hCNT2 mRNA levels. Selected LETFs are involved in the regulation of SLC28 genes in an isoform-specific manner. HNF4 alpha is a major determinant of SLC28A1 expression, whereas C/EBP alpha and HNF3 gamma modulate SLC28A2 gene expression. (c) 2006 Elsevier Inc. All rights reserved.