title: The thyroid hormone analogue SKF-94901 and iodothyronine binding sites in mammalian tissues: differences in cytoplasmic binding between liver and heart.
abstract: 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 (Kd approximately 3 mumol/l), and to nuclear extracts (Kd approximately 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 (Kd, 22.7 +/- 10.4 nmol/l) and liver tissue (Kd, 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 greater than T4 greater than 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 less than 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.
authors.affiliation: Ewen Downie Metabolic Unit, Alfred Hospital, Melbourne, Victoria, Australia.
authors.forename: J W
authors.initials: JW
authors.lastname: Barlow
authors.forename: L E
authors.initials: LE
authors.lastname: Raggatt
authors.forename: C F
authors.initials: CF
authors.lastname: Lim
authors.forename: E
authors.initials: E
authors.lastname: Kolliniatis
authors.forename: D J
authors.initials: DJ
authors.lastname: Topliss
authors.forename: J R
authors.initials: JR
authors.lastname: Stockigt
mesh_terms: D000818:Animals; D001665:Binding Sites; D002457:Cell Extracts / Q000032:analysis; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D007457:Iodine Radioisotopes; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008252:Macaca fascicularis / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D011988:Receptors, Thyroid Hormone / Q000378:metabolism / Q000648:ultrastructure; D013970:Thyronines / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D002457:Cell Extracts; D007457:Iodine Radioisotopes; D011988:Receptors, Thyroid Hormone; C050835:SK&F 94901; D013970:Thyronines; D014284:Triiodothyronine