title: Contribution of CNT1 and ENT1 to ribavirin uptake in human hepatocytes.
abstract: The objective of this study was to investigate the contributions of a sodium-dependent concentrative nucleoside transporter (CNT) 1 and an equilibrative nucleoside transporter (ENT) 1 to ribavirin uptake in human hepatocytes. The initial studies in oocytes expressing CNT1 and ENT1 showed increases in ribavirin uptake, indicating that ribavirin was a substrate for both CNT1 and ENT1. The CNT1- and ENT1-mediated ribavirin uptake showed concentration dependency with the following kinetics parameters: Km 26.3 μM and Vmax 426.2 fmol/min/oocyte for CNT1; Km 70.5 μM and Vmax 134.3 fmol/min/oocyte for ENT1. Ribavirin uptake clearance in six human hepatocytes ranged from 21.3 to 300.7 μL/min. Estimation of the contributions of CNT1 and ENT1 to the hepatic uptake of ribavirin by using a relative activity factor method indicated that the relative contribution of ENT1 to the ribavirin uptake was 82.8 ± 3.9%. Real-time polymerase chain reaction analysis of CNT1 and ENT1 expressions in the hepatocytes showed that ENT1 mRNA expression was closely correlated with ribavirin uptake (R = 0.95, P = 0.003) while CNT1 was not. The findings indicated that ENT1 was the major transporter controlling the hepatic uptake of ribavirin.
authors.affiliation: College of Pharmacy, Dankook University, 119 Dandaero, Cheonan, Chungnam, 330-714, Korea.
authors.forename: Min-Koo
authors.initials: MK
authors.lastname: Choi
authors.forename: Min-Hye
authors.initials: MH
authors.lastname: Kim
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism*; D033721:Equilibrative Nucleoside Transporter 1 / Q000096:biosynthesis*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D012254:Ribavirin / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D033721:Equilibrative Nucleoside Transporter 1; D026901:Membrane Transport Proteins; C438649:SLC29A1 protein, human; C065171:cif nucleoside transporter; D012254:Ribavirin