Mendel C M, Cavalieri R R, Weisiger R A
Cardiovascular Research Institute, University of California, San Francisco.
Am J Physiol. 1988 Aug;255(2 Pt 1):E110-9. doi: 10.1152/ajpendo.1988.255.2.E110.
To investigate the mechanism by which thyroxine (T4) in plasma enters hepatic cells, we measured the rate constants for uptake of free T4 by the perfused rat liver and for dissociation of T4 from its plasma binding proteins. Quantitative autoradiography of liver lobules after perfusion with [125I]T4 indicated an apparent rat constant for removal of free T4 from the sinusoids of at least 1.1 +/- 0.2 s-1. Single-pass extraction of T4 from human serum was 10.6 +/- 1.7% at physiological flow rates (1 ml.min-1.g liver-1). Rate constants for dissociation of T4 from plasma binding proteins at 37 degrees C (determined by rapid filtration) were 0.017 +/- 0.002 s-1 for human thyroid hormone-binding globulin, 0.080 +/- 0.015 s-1 for human thyroid hormone-binding prealbumin, and greater than 0.5 s-1 for human albumin. To investigate the factors that determine the concentration of T4 within hepatic cells, we analyzed the above data together with data reported in the literature on the equilibrium-binding constants and the rate constant for cellular metabolism of T4. Analysis of all of these data using a previously published mathematical model leads to the following conclusions for the physiological state: 1) metabolism, not uptake, is rate limiting to removal of T4 from plasma by the liver; 2) binding equilibrium is present in the intrahepatic plasma; 3) intracellular T4 is in equilibrium with the free T4 pool in plasma (and maintenance of this equilibrium may be an important function of plasma thyroid hormone-binding proteins); and 4) the concentration of T4 within the liver is proportional to the concentration of free T4 in the plasma. Our data do not allow us to determine definitively whether hepatic uptake of T4 occurs only from the free T4 pool in plasma or also from the protein-bound pool by interaction of one or more of the binding proteins with the liver cell. However, mathematical analysis indicates that this distinction is irrelevant to steady-state intracellular hormone concentrations when equilibrium exists between the plasma and cytosolic pools of hormone.
为了研究血浆中的甲状腺素（T4）进入肝细胞的机制，我们测定了灌注大鼠肝脏摄取游离T4的速率常数以及T4与其血浆结合蛋白解离的速率常数。用[125I]T4灌注后对肝小叶进行定量放射自显影显示，从肝血窦中清除游离T4的表观速率常数至少为1.1±0.2 s-1。在生理流速（1 ml·min-1·g肝脏-1）下，人血清中T4的单次通过提取率为10.6±1.7%。37℃时T4从血浆结合蛋白解离的速率常数（通过快速过滤测定），人甲状腺激素结合球蛋白为0.017±0.002 s-1，人甲状腺激素结合前白蛋白为0.080±0.015 s-1，人白蛋白大于0.5 s-1。为了研究决定肝细胞内T4浓度的因素，我们将上述数据与文献中报道的关于T4的平衡结合常数和细胞代谢速率常数的数据一起进行了分析。使用先前发表的数学模型对所有这些数据进行分析，得出了关于生理状态的以下结论：1）代谢而非摄取是肝脏从血浆中清除T4的限速因素；2）肝内血浆中存在结合平衡；3）细胞内T4与血浆中的游离T4池处于平衡状态（维持这种平衡可能是血浆甲状腺激素结合蛋白的一项重要功能）；4）肝脏内T4的浓度与血浆中游离T4的浓度成正比。我们的数据无法明确确定肝脏摄取T4是仅来自血浆中的游离T4池，还是也通过一种或多种结合蛋白与肝细胞的相互作用来自蛋白结合池。然而，数学分析表明，当激素的血浆池和胞质池之间存在平衡时，这种区别与稳态细胞内激素浓度无关。
