Expression cloning of the cDNA encoding intracellular transporters of thyroid hormones.

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1) TNF, IL-1, and IL-6 enhanced nuclear uptake of tetrac and thyroxine (T4). The effects were more notable in pituitary cells than in hepatic cells. Tetrac may be responsible for the reduced serum TSH level despite reduced levels of serum triiodothyronine (T3) and T4 in sick euthyroid syndrome in which elevated production of these cytokines enhances pituitary nuclear transport of tetrac. These data also indicate the different nuclear uptake mechanisms between T3 and tetrac or T4.2) SK＆F L-949Ol shows more potent thyromimetic activity in liver than in pituitary gland or heart when administered to rats. Using cultured rat hepatoma cells (dRLH-84) and rat pituitary tumor cells (GH3), we found that SK＆F L-94901 is more effectively transported to nuclear thyroid hormone receptors in hepatic cells than in pituitary cells and therefore shows liver-selective thyromimetic activity. Other than SK＆F L-94901, we also found various new compounds that show liver-selective thyromimetic activities. These compounds, when administered to rats, showed hypolipidemic effects without cardiac or pituitary action.3) cDNA encoding the cytosolic thyroid hormone binding protenis that regulate transport of T3 from cytosol to nuclei were isolated from human fetal brain cDNA library. This protein resides in cytosol and modifies thyroid hormone action. We will continue isolation of cellular transporters of thyroid hormones from other tissues, in order to design drugs that discriminate differences in structures of the transporters among various cell types.