BIOLOGICAL ACTIVITY OF NOVEL THYROID HORMONE ANALOGUES: ROLE OF Na+ TAUROCHOLATE COTRANSPORTING POLYPEPTIDE IN LIVER SELECTIVITY

Background: The interest in the potential effect of thyromimetics in lowering serum cholesterol is growing. Thyroid hormone actions on lipid metabolism are exerted in the liver and mediated by the T3 receptor TRβ1. The creation of molecules transported into hepatocytes by liver-specific transporters can increase the liver selectivity of thyromimetics. Sodium taurocholate co-transporting polypeptide (NTCP), a solute carrier protein primarily expressed on the basolateral membrane of hepatocytes, is particularly interesting. Objectives: The role of NTCP in the liver preferential uptake of a series of new thyromimetics was analysed. Methods: The compounds to test (KB141, KB5588, KB6628, KB6823, KB3488, KB3493, KB3495, KB4933, KB4956, KB5035, KB5160, KB5359, KB5525, KB5526, KB5866, KB6594, KB8038) were synthesised at Karo Bio AB. To explore the effect of NTCP on the nuclear availability of each compound, COS1 cells were co-transfected with TRβ1, NTCP, a construct coding for a TRE-dependent luciferase reporter and a control renilla reporter. Two days after transfection, cells were incubated for 24 h with 0.1–1000 nM of each compound. Incubation with the same concentrations of T3 was added as a control. The luciferase/renilla ratio was the measure of the compound transcriptional activity. Results: Like T3, KB141, KB5588, KB3488 and KB6823 demonstrated no differences in transcriptional activity in the absence or presence of NTCP. KB6628, KB5035, KB5866, KB5160 and KB4956 showed a 1.5-fold higher activity in cells transfected with NTCP compared to cells transfected with empty pcDNA3 vector. KB3493, KB3495, KB5359, KB5525, KB5526, KB4933, KB6594 and KB8038 showed an even greater difference as they had no activity in the absence of NTCP and a fourfold higher activity in the presence of NTCP. Conclusions: NTCP is an attractive transporter to target thyromimetics to the liver.