Mechanism of liver-selective thyromimetic activity of SK&F L-94901: evidence for the presence of a cell-type-specific nuclear iodothyronine transportprocess

The thyromimetic compound SK&F L-94901 shows more potent thyromimetic activ ity in the liver than in the pituitary gland or heart when administered to rats. The mechanisms of liver-selectivity of SK&F L-94901 were examined usi ng cultured rat hepatoma cells (dRLH-84) and rat pituitary tumor cells (GH3 ), both of which showed saturable cellular uptake of tri-iodothyronine (T-3 ). When isolated nuclei with partial disruption of the outer nuclear membra ne were used, SK&F L-94901 competed for [I-125]T-3 binding to nuclear recep tors almost equally in dRLH-84 and GH3 cells. SK&F L-94901 also did not dis criminate thyroid hormone receptors (TR) alpha 1 and beta 1 in terms of bin ding affinity and activation of the thyroid hormone responsive element. In intact cells, however, SK&F L-94901 was a more potent inhibitor of nuclear [I-125]T-3 binding in dRLH-84 cells than in GH3 cells at an early phase of the nuclear uptake process and after binding equilibrium. These data sugges t that SK&F L-94901 is more effectively transported to nuclear TRs in hepat ic cells than in pituitary cells and therefore shows liver-selective thyrom imetic activity. In conclusion, SK&F L-94901 discriminates hepatic cells an d pituitary cells at the nuclear transport process. The cellular transporte rs responsible for this discrimination were not evident.