10/09/2017 - Role of transporters in drug toxicity
Jani M, Beéry E, Heslop T, Tóth B, Jagota B, Kis E, Kevin Park B, Krajcsi P, Weaver RJ.
Toxicol In Vitro. 2018 Feb;46:189-193. doi: 10.1016/j.tiv.2017.10.012. Epub 2017 Oct 9.
The transport of bile acids facilitated by NTCP is an important factor in establishing bile flow. In this study, we examine the kinetics associated with human NTCP-dependent transport of two quantitatively important bile acids comprising the human bile acid pool, chenodeoxycholic acid and glycine-chenodeoxycholate, and secondary bile salt, 3-sulfo-glycolithocholate of potential toxicological significance. The study employed human NTCP overexpressing Chinese Hamster Ovary cells and results compared with taurocholate, a prototypical bile salt commonly used in transporter studies. GCDC and 3S-GLC but not CDCA were transported by NTCP. The efficient uptake of GCDC, TCA and 3S-GLC by NTCP enabled the determination of kinetics. GCDC displayed a lower KM (0.569±0.318μM) than TCA (6.44±3.83μM) and 3S-GLC (3.78±1.17μM). The apparent CLint value for GCDC was 20-fold greater (153±53μl/mg protein/min) than the apparent CLint for TCA (6.92±4.72μl/mg protein/min) and apparent CLint for 3S-GLC (8.05±1.33μl/mg protein/min). These kinetic results provide important complementary data on the substrate selectivity and specificity of NTCP to transport bile acids. NTCP transports GCDC with greater efficiency than TCA and has the same efficacy for 3S-GLC and TCA.open_in_new Read the Source
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