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1 Pharmaceutics, University of Washington, Seattle, Washington, United States
2 Cellzdirect, Pittsboro, North Carolina, United States
3 Biochemistry and Molecular Biology, Institute of Biomedicine, University of Barcelona, Barcelona, Spain
4 Department of Gastroenterology, Johns Hopkins University, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: jash{at}u.washington.edu.
We previously reported that both the concentrative (hCNT) and equilibrative (hENT) nucleoside transporters are expressed in the human liver (21). Here we report a study that investigated the expression of these transporters (transcripts and proteins) and their role in the hepatobiliary transport of nucleosides/nucleoside drugs using sandwich-cultured human hepatocytes. In the hepatic tissue, the rank order of the mRNA expression of the transporters was hCNT1
hENT1>>hENT2hCNT2>hCNT3. In sandwich-cultured hepatocytes, the mRNA expression of hCNT2 and hENT2 was comparable to that in hepatic tissue, while the expression of corresponding transporters in the two-dimensional hepatocyte cultures was lower. Colocalization studies demonstrated predominant localization of these transporters at the sinusoidal membrane and of hENT1, hCNT1 and hCNT2 at the canalicular membrane. In the sandwich-cultured hepatocytes, ENTs were the major contributors to the transport of thymidine (hENT1, 63%; hENT2, 23%) or guanosine (hENT1, 53%; hENT2, 24%) into the hepatocytes followed by hCNT1 (10%) for thymidine or hCNT2 (23%) for guanosine. While ribavirin was predominately transported (89%) into the heptocytes by hENT1, FIAU was transported by both hENT1 (30%) and hCNTs (61%). The extensively metabolized natural nucleosides were not effluxed into the bile while significant biliary-efflux was observed of FIAU (19%), ribavirin (30%) and formycin B (35%). We conclude that the hepatic activity of hENT1 and hCNT1/2 transporters will determine the in vivo hepatic distribution and therefore the efficacy and/or toxicity of nucleoside drugs used to treat hepatic diseases.
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