Rapid effects of the flavonoid EMD 21388 on serum thyroid hormone binding and thyrotropin regulation in the rat

Naturally occurring and synthetic flavonoids are potent inhibitors of thyroid hormone 5'-deiodination and binding to human serum transthyretin (TTR) in vitro. We now describe the inhibitory effect of the most potent flavonoid, 3-methyl-4',6-dihydroxy-3',5'-dibromo-flavone (EMD 21388), on the serum protein binding of T4 and T3 and subsequent alterations of pituitary-thyroid function in the rat. Eight to 10 mumol/liter EMD 21388 added to pooled rat serum completely displaced 125I]T4 or 125I]T3 binding from TTR, the major thyroid hormone-binding protein in the rat, and markedly increased the percentages of free T4 and T3, measured by equilibrium dialysis. One to 4 h after the ip administration of 2 mumol EMD 21388/100 g BW to euthyroid rats, 125I]T4 and 125I]T3 binding to TTR decreased, serum T4 and T3 concentrations decreased, and the percentages of free T4 and free T3 increased. No changes were observed in the free T4 and free T3 concentrations. Serum TSH concentrations decreased at 1 h and were very low thereafter. EMD 21388 administration did not affect the elevated serum TSH concentrations in hypothyroid rats, strongly suggesting that the flavonoid does not directly affect TSH secretion. No changes were observed in hepatic type I 5'-deiodinase in euthyroid rats and pituitary type I and type II 5'-deiodinase in euthyroid and hypothyroid rats after EMD 21388 administration. We conclude that the ip administration of EMD 21388 to euthyroid rats inhibits T4 and T3 binding to TTR, with subsequent increases in the percentages of free T4 and free T3 and decreased serum T4 and T3 concentrations. The decrease in the serum TSH concentration was possibly due to transcient increases in the serum free T4 and/or free T3 concentrations, resulting in increased pituitary thyroid hormone content.