Flavonoid effects on transport, metabolism and action of thyroid hormones.

Flavonoids are potent non-toxic ITH deiodinase inhibitors in microsomal membranes, and intact rat hepatocytes. Flavonoids are specific high affinity competitors for L-T4-binding to human TBPA, weaker antagonists in the rT3-5'deiodinase reaction, and very poor inhibitors of T3 binding to the nuclear T3 receptor. Optimized flavonoid antagonists exhibit an ITH bio-isosteric structure and conformation. The T4-binding site of hTBPA is a useful "receptor model" for type I deiodinase in computer aided drug design of flavonoid antagonists with improved pharmacological characteristics, bio-availability, and target-specificity for ITH-binding sites. The optimized T4-antagonistic flavonoid EMD 21388 given for 4 days in a 10-fold dose compared to the euthyroid T4-substitution dose does not alter serum levels of T4, T3. and TSH in rats. However, this dose of EMD 21388 results in a "tissue hyperthyroidism" in rat liver, which is not reflected by serum hormone levels and not monitored by altered pituitary TSH secretion. Many questions arise from these studies: Does EMD 21388 alter a) T3 degradation in rat liver, b) ITH transport across the liver plasma membrane c) ITH compartmentalization in the liver? Are these effects dependent on dose, application form and duration of the treatment? EMD 21388 is a suitable model compound to address these questions in future experiments. These studies furthermore will both elucidate the role of ITH deiodination for tissue specific expression of thyroid hormone action and effect as well advance the knowledge of specific interaction of flavonoids with biomolecules involved in mammalian intermediary metabolism. The dual effect of EMD 21388 as inhibitor of intracellular ITH deiodinase and as competitor of T4 binding to the serum transport protein TBPA may allow the design of a potent antithyroidal agent with extra-thyroidal mechanism of action in the process of T4 bioactivation to the thyromimetically active T3.