In many respects, T4 can be regarded as a prohormone for the more potent hormone, T3. Most of the TH bound to receptors is in the form of T3, either secreted into the circulation by the thyroid gland or derived from T4 to T3 conversion by 5' monodeiodinases (see Chapter 3C). There are three distinct deiodinases- type I, type II, and type III (19, 20). The distribution and regulation of these enzymes can have important effects on TH action. For example, Type II deiodinase has high affinity for T4 (Kd in the nanomolar range) and is found primarily in the pituitary gland, brain, and brown fat where conversion of T4 to T3 modulates the intracellular concentration of T3. Thus, tissues that contain type II deiodinase can respond differently to a given circulating concentration of T4 (by intracellular conversion to T3) than organs that only can respond to T3 (21, 22). Additionally, it appears that both type 1 and type II deiodinase regulate the circulating T4 and T3 levels . Recently, MCT8, OATP-1, and System L amino acid transporters have been identified as TH transporters which regulate T4 and T3 uptake into cells . Mutations in the former have been involved in a number of syndromes of x-linked mental retardation and neurologic deterioration .

T3 binds to its receptors with approximately 10-15 fold higher affinity than T4. The dissociation constants for liver nuclear receptors measured in vitro are 2 x 10-9 M for T4 and 2 x 10-10 M for T3. Nuclear receptors are approximately 75% saturated with TH in brain and pituitary and 50% saturated with TH in liver and kidney. It is notable that the extent of TH receptor occupancy varies in different tissues, providing a mechanism for alterations in circulating TH levels to alter receptor activity. In contrast to the related steroid hormone receptors, TRs are mostly nuclear both in the absence and presence of TH (26,157). In fact, TH receptors are tightly associated with chromatin (28 – 30), consistent with their proposed role as DNA-binding proteins that regulate gene expression.