Mechanism of liver-selective thyromimetic activity of SK&F L-94901: evidence for the presence of a cell-type-specific nuclear iodothyronine transport process.
The thyromimetic compound SK&F L-94901 shows more potent thyromimetic activity 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 using 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 membrane were used, SK&F L-94901 competed for [(125)I]T(3) binding to nuclear receptors almost equally in dRLH-84 and GH3 cells. SK&F L-94901 also did not discriminate thyroid hormone receptors (TR) alpha1 and beta1 in terms of binding affinity and activation of the thyroid hormone responsive element. In intact cells, however, SK&F L-94901 was a more potent inhibitor of nuclear [(125)I]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 suggest that SK&F L-94901 is more effectively transported to nuclear TRs in hepatic cells than in pituitary cells and therefore shows liver-selective thyromimetic activity. In conclusion, SK&F L-94901 discriminates hepatic cells and pituitary cells at the nuclear transport process. The cellular transporters responsible for this discrimination were not evident.
Ichikawa
K
K
Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto-City 390-8621 Japan. kazuichi@hsp.md.shinshu-u.ac.jp
Miyamoto
T
T
Kakizawa
T
T
Suzuki
S
S
Kaneko
A
A
Mori
J
J
Hara
M
M
Kumagai
M
M
Takeda
T
T
Hashizume
K
K
D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D007457:Iodine Radioisotopes; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013970:Thyronines / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C113777:2-amino-3-(3,5-dibromo-4-(4-hydroxy-3-(6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxyl)-phenyl)-propionic acid; D007457:Iodine Radioisotopes; D011422:Propionates; D011724:Pyridazines; D011988:Receptors, Thyroid Hormone; D013970:Thyronines