Steady state model of 3,5,3'-triiodothyronine transport in liver predicts high cellular exchangeable hormone concentration relative to in vitro free hormone concentration.
The hepatic nuclear receptor for T3 is known to be approximately 50% saturated in vivo. Since the receptor dissociation constant (Kd) is 1 nM, and since 50% receptor occupancy occurs when the concentration of free ligand in the nucleus is 1 nM, the concentration of free T3 in the hepatic nucleus is also approximately 1 nM or about 200-fold greater than the concentration of free T3 in human serum, as measured in vitro by equilibrium dialysis. However, previous tracer kinetic studies have shown that T3 is available for transport from both the circulating albumin- and thyroid hormone-binding globulin-bound pools in plasma. Since the plasma proteins per se do not significantly exit the hepatic microcirculation on a single pass, the protein-bound hormone is operationally available for transport into liver via a proposed mechanism of enhanced dissociation caused by interactions between the plasma proteins and the hepatic microcirculation. These considerations raise the question as to whether the dissociation of T3 from serum proteins is sufficiently enhanced to allow for enrichment in the hepatic pools of exchangeable hormone that can generate 50% receptor occupancy. The present studies present a physiologically based steady state model of T3 transport and distribution in liver. All parameters of the model pertain to physiologically discrete pathways of hormone, plasma protein, or plasma flux through the liver. The rate constants were estimated from previously reported tracer kinetic transport data in rat liver in vivo using rat and human serum proteins. A computer program in BASIC for steady state analysis is presented. The results of the stimulation studies are as follows. The concentration of cellular exchangeable T3 in liver is predicted to be approximately 2 log orders greater than the concentration of free T3 measured in vitro, but approximately equal to the concentration of free T3 predicted to exist in the hepatic nucleus; thus, the high degree of hepatic nuclear T3 receptor occupancy is compatible with the model that T3 is available for transport into liver from the circulating serum protein-bound pools. The concentration of cellular exchangeable T3 is governed primarily by the concentration of plasma exchangeable T3 (and membrane transport and cellular metabolism of T3) and is predicted to be independent of changes in the concentration of cytosolic T3-binding proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D003600:Cytosol / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation; D008433:Mathematics; D008954:Models, Biological; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D012984:Software; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism*
D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine