The role of the iodothyronine deiodinases in the physiology and pathophysiology of thyroid hormone action.

Thyroxine (T4) is a prohormone and must be activated to 3,5,3' triodothyronine (T3) by either the type 1 (D1) or 2 (D2) selenodeiodinase. A third deiodinase (D3) inactivates T3 or T4 by removal of an inner ring iodine. These reactions require both a deiodinase enzyme and a cofactor, probably a thiol, to reduce the oxidized selenolyl group in the active center of each deiodinase. Thus, deiodination rates depend on both the enzyme and cofactor. The source of most of the circulating T3 is D1-mediated, while D2 provides nuclear receptor-bound hormone. Using sensitive and specific assays, it has become apparent that both D2 and D3 are widespread throughout vertebrate tissues. The complex interactions between the activating D2 and the inactivating D3 in tissues expressing these two enzymes determine the intracellular T3 concentration. This provides enormous flexibility for both developmental and tissue regeneration processes, allowing exquisite control of intracellular T3 concentrations. The endogenous factors regulating the activity of these enzymes, such as the hedgehog proteins, FoxO3, or the wnt/β catenin pathway together with the actions of thyroid hormone transporters, direct adjustments of nuclear receptor bound T3 which in turn can control the balance between cellular proliferation and differentiation. Their actions provide dynamic flexibility to what appears on the surface to be a very static hormonal system.