Displacement of T4 from transthyretin by the synthetic flavonoid EMD 21388 results in increased production of T3 from T4 in rat dams and fetuses.
EMD 21388 displaces T4 from circulating transthyretin, is a potent in vitro inhibitor of outer-ring deiodination (5'D) of T4 and affects thyroid hormone secretion. To study its extrathyroidal effects on the thyroid hormone status of pregnant dams and their fetuses, we treated the dams with methimazole and infused them with T4 and with either 2.5 mg EMD 21388/rat per day [(EMD(+)], or placebo solution [EMD(-)]. EMD reduced total T4 and T3 in the maternal circulation, but free T4 increased and free T3 decreased. The total amount of T3 generated from T4 in the maternal compartment increased. Placental T3 also increased in EMD(+) animals, T4 remaining the same. EMD also reached the fetal circulation. The total fetal extrathyroidal T4 pool decreased to half that of EMD(-) fetuses, whereas T3 increased 1.8-fold, thus mitigating fetal T3 deficiency, especially in the lung. Thus, if the maternal supply of T4 is kept constant, EMD mitigates the T3 deficiency of many tissues of the hypothyroid fetus. Most of the effects of this dose of EMD could result from the displacement of T4 from circulating transthyretin. Liver 5'D-I activity did not decrease, but actually increased by 40% in dams and fetuses. The enhanced transfer of T4 into tissues would also increase the amount of substrate available to 5'D-I, leading to an increased amount of T3 in maternal and fetal pools. This had not been anticipated from the changes in circulating T4 and T3, whether maternal or fetal, total or free.
Unidad de Endocrinología Molecular, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
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D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D008713:Methimazole / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011228:Prealbumin / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*; D013974:Thyroxine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D011228:Prealbumin; D014284:Triiodothyronine; C057452:3-methyl-4',6-dihydroxy-3',5'-dibromoflavone; D008713:Methimazole; D007453:Iodide Peroxidase; D013974:Thyroxine