Document Detail


ENT1, a ribavirin transporter, plays a pivotal role in antiviral efficacy of ribavirin in a hepatitis C virus replication cell system.
MedLine Citation:
PMID:  22232287     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We previously showed that equilibrative nucleoside transporter 1 (ENT1) is a primary ribavirin transporter in human hepatocytes. However, because the role of this transporter in the antiviral mechanism of the drug remains unclear, the present study aimed to elucidate the role of ENT1 in ribavirin antiviral action. OR6 cells, a hepatitis C virus (HCV) replication system, were used to evaluate both ribavirin uptake and efficacy. The ribavirin transporter in OR6 cells was identified by mRNA expression analyses and transport assays. Nitrobenzylmercaptopurine riboside (NBMPR) and micro-RNA targeted to ENT1 mRNA (miR-ENT1) were used to reduce the ribavirin uptake level in OR6 cells. Our results showed that ribavirin antiviral activity was associated with its accumulation in OR6 cells, which was also closely associated with the uptake of the drug. It was found that the primary ribavirin transporter in OR6 cells was ENT1 and that inhibition of ENT1-mediated ribavirin uptake by NBMPR significantly attenuated the antiviral activity of the drug as well as its accumulation in OR6 cells. The results also showed that even a small reduction in the ENT1-mediated ribavirin uptake, achieved in this case using miR-ENT1, caused a significant decrease in its antiviral activity, thus indicating that the ENT1-mediated ribavirin uptake level determined its antiviral activity level in OR6 cells. In conclusion, our results show that by facilitating its uptake and accumulation in OR6 cells, ENT1 plays a pivotal role in the antiviral effectiveness of ribavirin and therefore provides an important insight into the efficacy of the drug in anti-HCV therapy.
Authors:
Minami Iikura; Tomomi Furihata; Misa Mizuguchi; Miki Nagai; Masanori Ikeda; Nobuyuki Kato; Akihito Tsubota; Kan Chiba
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-09
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  56     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-02-16     Completed Date:  2012-08-24     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1407-13     Citation Subset:  IM    
Affiliation:
Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
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MeSH Terms
Descriptor/Qualifier:
Antiviral Agents / pharmacology*
Biological Transport / drug effects
Blotting, Western
Cell Line, Tumor
Equilibrative Nucleoside Transporter 1 / antagonists & inhibitors*,  metabolism
Genes, Reporter
Hepacivirus / drug effects,  physiology*
Hepatocytes / drug effects*,  metabolism
Humans
Luciferases
MicroRNAs / genetics,  metabolism
RNA, Messenger / genetics*
Ribavirin / pharmacology*
Thioinosine / analogs & derivatives,  pharmacology
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Equilibrative Nucleoside Transporter 1; 0/MicroRNAs; 0/RNA, Messenger; 0/SLC29A1 protein, human; 36791-04-5/Ribavirin; 38048-32-7/4-nitrobenzylthioinosine; 574-25-4/Thioinosine; EC 1.13.12.-/Luciferases
Comments/Corrections

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