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The thyroid hormone analogue SKF-94901 and iodothyronine binding sites in mammalian tissues: Differences in cytoplasmic binding between liver and heart

The thyroid hormone analogue, SKF-94901 exhibits greater thyromimetic activity in the liver than in the heart. This difference in activity may reflect heterogeneity in the affinity of SKF-94901 for different forms of the T₃ receptor. A difference in extranuclear transport of the analogue could also account for the different response of these two tissues. To distinguish between these possibilities we have examined the binding of SKF-94901 to membrane, cytosolic and nuclear preparations from liver and heart of the primate, Macaca fascicularis. Uptake of SKF-94901 into H₄ liver cells was low. Binding of [¹²⁵I]T₃ to cell membrane preparations (K_d 3 µmol/l), and to nuclear extracts (K_d 0.2 nmol/l was displaceable by SKF-94901 with a potency 2-5% that of T₃ in each case. No significant difference was observed between liver and heart for SKF-94901 binding to membranes or nuclear extract. With cytosol, [¹²⁵I]T₃ binding was identical in heart (K_d, 22.7±10.4 nmol/l) and liver tissue (K_d, 30.3±11.1 nmol/l). In liver, and in cardiac cytosol after preliminary washing to remove serum, iodothyronine potency was in the order T₃ > T₄ > rT₃. The ratio of SKF-94901 to T₃ concentrations which gave 50% displacement was 15.9±6.8 in the liver; and 152.3±89.1 in the heart (p<0.05). The selective tissue activity of SKF-94901 may be related to a reduced affinity of the analogue for the cytosolic binding proteins in the heart, rather than a difference in affinity for various forms of the T₃ receptor.

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