THE THYROID-HORMONE ANALOG 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 H-4 liver cells was low. Binding of [I-125]T3 to cell membrane preparations (K(d) almost-equal-to 3-mu-mol/l), and to nuclear extracts (K(d) almost-equal-to 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, [I-125]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.