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Drug competition for intracellular triiodothyronine-binding sites

Barlow JW, Curtis AJ, Raggatt LE, Loidl NM, Topliss DJ. Stockigt JR. Drug competition for intracellular triiodothyronine-binding sites. Eur J Endocrinol 1944;130:417–21. ISSN 0804–4643

A variety of substances, including frusemide, non-esterified fatty acids (NEFAs) and non-steroidal antiinflammatory drugs (NSAIDs), can compete for triiodothyronine (T₃)-binding sites in serum and at the cell surface. We examined the competitive potency of these agents at intracellular T₃-binding sites in order to assess their potential to act as T₃ antagonists. Competition for [¹²⁵I]T₃ binding was determined using hydroxyapatite separation in cytosols and nuclear extracts prepared from livers of Macaca fascicularis. The T₃ affinities were 15.8 ± 1.2 nmol/l in cytosol and 0.23 ± 0.02 nmol/l in nuclear extract. Does–response curves were analysed by a four-parameter sigmoid curve-fitting program to determine competitor potency. The nineteen agents tested included various NSAIDs, NEFAs, non-bile acid cholephils (NBACs), frusemide, amiodarone and the flavonoid EMD 21388. In nuclear extract the most active competitors were linoleic acid (8.5 µmol/l) and linolenic acid (7.8 µmol/l), Potencies of NSAIDs varied between 66 µmol/l (meclofenamic acid) and 525 µmol/l (diclofenac). In cytosol, NEFAs were less potent but NSAIDs were stronger competitors than in nuclear extract. Half-inhibitory potencies in cytosol were between 13.2 µmol/l (meclofenamic acid) and 63.1 µmol/l (flufenamic acid). The NBAC bromosulphthalein was one of the most potent inhibitors in both cytosol and nuclear extract. When expressed relative to T₃, diclofenac was a more effective competitor in cytosol than it was in nuclear extract. Amiodarone and EMD 21388 were without effect both in cytosol and nuclear extract. Frusemide (759 µmol/l) was weakly active in cytosol only. The action of T₃ was assessed by measuring secretion of sex hormone-binding globulin (SHBG) in Hep-G2 cells. After 3 days with total T₃ (0.1 µmol/l), SHBG was 155 ± 15% of the control. Amiodarone (100 µmol/l) and meclofenamic acid (100 µmol/l) were cytotoxic. Bromosulphthalein (10 µmol/l), one of the most potent competitors at both the cytoplasmic and the nuclear level, did not influence the T₃-induced rise in SHBG secretion. None of the drugs tested affected the magnitude of maximal induction of SHBG by T₃. Substances that compete for serum and cell surface T₃-binding sites are also weak competitors for intracellular T₃-binding proteins, although the heirarchy of potency differs. Frusemide and diclofenac, with a greater relative potency for cytosolic binding than nuclear binding, may have potential use in investigating the function of cytosolic T₃-binding. Amiodarone shows no binding activity and is not a hormone antagonist in primate hepatic tissue.

John W Barlow, Ewen Downie Metabolic Unit, Alfred Hospital, Commercial Road, Melbourne, Victoria 3181, Australia

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