Stereospecificity of Triiodothyronine Transport into Brain, Liver, and Salivary Gland: Role of Carrier- and Plasma Protein-Mediated Transport*

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Abstract
The stereospecificity of T3 transport through the walls of the brain capillary, i.e. the blood-brain barrier (BBB), and the salivary gland capillary and through the hepatocyte plasma membrane was studied with a tissue-sampling single injection technique in rats. In the absence of plasma proteins, the ED50 of inhibition of the saturable transport of [125I]L-T3 through the BBB was 1 .mu.M for unlabeled L-T3 and 9 .mu.M for unlabeled D-T3. The brain extraction of [125I]D-T3, 5.9 .+-. 0.1% (.+-.SE), was about one third that of [125I]L-T3. Conversely, no saturable and no stereospecific T3 transport was observed for the salivary gland capillary, which, unlike the brain capillary, is porous. The hepatic extraction of T3 was minimally stereospecific in the absence of plasma proteins. In the presence of 5 g/dl bovine albumin, the fraction of circulating D- or L-T3 that was available for transport into liver (50-100%) was many-fold greater than the fraction that was free in vitro (.apprx. 2%); therefore, both D-T3 and L-T3 were available for uptake by liver from the circulating albumin-bound pool. This plasma protein-mediated transport of T3 is believed to represent a process of enhanced dissociation of T3 from the albumin-binding site, since the plasma protein per se is not significantly taken up by liver on a single pass. However, in the presence of 5 g/dl bovine albumin, the extravascular hepatic extraction of [125I]D-T3 (50 .+-. 2%) was nearly half that for [125I]T3 (93 .+-. 12%), although no significant difference in the in vitro binding of [125I]D-T3 and [125I]L-T3 to 5 g/dl bovine albumin was found with equilibrium dialysis. In addition, the isoelectric point of bovine albumin bound to [125I] L-T3 (5.1) was higher than that of bovine albumin bound to [125I] D-T3 (5.0), as determined by isoelectric focusing, which indicates that the surface of the bovine albumin molecule is slightly more positive when the protein binds L-T3 as opposed to D-T3. The isoelectric focusing and in vivo transport data together suggest that the interaction between the surfaces of the plasma protein and the hepatic microcirculation that is presumed to cause enhanced hormone dissociation from the protein-binding site is electrostatic in nature. These studies (1) show that the BBB thyroid hormone transport system is sharply stereospecific, and this property is probably a major factor underlying the low biological potency of D-T3 in brain; and (2) provide the first evidence for stereospecificity of plasma protein-mediated transport of hormones into tissues in vivo.