Spatially and Blood Flow-Dependent Tissue Distribution of Thyroid Hormones by Plasma Thyroid Hormone Binding Proteins.

Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), are important in regulating thyroxine (T4) and triiodothyronine (T3). THBPs carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this question, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings. (1) Contrary to postulations that TTR and/or ALB are the major local TH contributors, the three THBPs may unload comparable amounts of T4 in Liver , a rapidly perfused organ; however, their contribution in Rest-of-Body (RB) , which is more slowly perfused, follows the order of abundance of T4TBG, T4TTR, and T4ALB. The T3 amounts unloaded in both compartments follow the order of abundance of T3TBG, T3ALB, and T3TTR. (2) Any THBP alone is sufficient to maintain spatially uniform TH tissue distributions. (3) The TH amounts unloaded by each THBP species are spatially dependent and nonlinear in a tissue, with ALB being the dominant contributor near the arterial end but conceding to TBG near the venous end. (4) Spatial gradients of TH transporters and metabolic enzymes may modulate these contributions, producing spatially invariant or heterogeneous TH tissue concentrations depending on whether the blood-tissue TH fluxes operate in near-equilibrium mode. In summary, our modeling provides novel insights into the differential roles of THBPs in local TH tissue distribution and homeostasis.