Transport of thyroxine bound to human prealbumin into rat liver

Abstract

The transport into rat liver of thyroxine (T4) bound to human prealbumin was studied with the use of sera obtained from patients with thyroid hormone-binding globulin (TBG) deficiency and with purified human prealbumin. The unidirectional extraction of 125I-T4 by liver was measured after rapid injection of isotope mixed in human serum into the portal vein of ketamine-anesthetized rats. The percentage of total serum T4 transported into liver was 47.6 +/- 5.2% in subjects with TBG deficiency, and this represented a 50% increase in hepatic T4 transport relative to control human serum. Since T4 is bound to albumin and to prealbumin in complete TBG deficiency, these results suggested that T4 bound to human prealbumin was transported into rat liver. This was confirmed using portal vein injections of human prealbumin at physiological concentrations (0.1-0.3 mg/ml). At these concentrations, T4 bound to human prealbumin was readily transported into liver. These studies suggest factors present in the liver microcirculation inhibit the binding of T4 to human prealbumin such that T4 bound to human prealbumin is highly transportable in liver; conversely, T4 bound to rat prealbumin is not transportable in rat liver. The inability of human prealbumin to sequester T4 in plasma may provide the basis for the selective advantage in humans of TBG, which does sequester T4 in plasma.

Thyroxine transport and distribution in Nagase analbuminemic rats.

“…Tissue uptake rate constants this high are not measureable by currently available techniques; the highest tissue uptake rate constant presently measureable appears to be on the order of 1-3 s-1 (3). Recent documentation that the rate constant for the uptake of T4 by rat liver is 2 1 s-' (3), contradicting a previous report to the contrary (5), is therefore also consistent with the indirect evidence that tissue uptake of T4 occurs via the pool of free hormone.…”

“…alytic mechanism exists within tissues to selectively release hormones from certain proteins but not from others (7). When interpreted in light of this hypothesis, previously obtained data have indicated that this special mechanism must act on the albumin-T4 complex in the rat, but not on the prealbumin-T4 complex (5).3 Ifthis hypothesis were true, analbuminemic rats would be expected to have greatly decreased rates of entry of T4 into tissues (< 1% of the observed hepatic uptake of T4 is considered to proceed via the pool offree T4 in this hypothesis, and none is considered to proceed via the pool of TBPAbound T4 [5]). Our data indicate that they do not.…”

“…This evidence includes the observations that the rate of tissue uptake of T4 has never been found to exceed the rate of spontaneous dissociation of T4 from its plasma-binding proteins within the tissue vasculature (1)(2)(3)(4). If tissue uptake of T4 does occur exclusively via the pool of free hormone, however, the tissue uptake rate constant acting on free T4 must be very high (-50 s-') to account for the observed data (3,5). That is, if 10% ofthe T4 in serum is taken up via the free pool by a tissue in a single transit, and ifonly 0.02% of the T4 in that serum is free, the tissue uptake rate constant must be high enough to allow the pool of free T4 to turn over 500 times during that transit.…”

“…This hypothesis assumes that spontaneous mechanisms of tissue uptake of free T4 cannot account for the observed rates of tissue uptake of T4 from serum, and that catalytic mechanisms that act to release T4 from certain binding proteins (but not from others) must therefore exist within the tissue vasculature. In the rat, these mechanisms are postulated to act on albumin-bound T4, but not on prealbumin-bound T4, such that the observed tissue uptake of T4 is postulated to occur almost entirely from the albumin-bound pool of T4 (5).…”

“…Although recent studies comparing the enhanced dissociation hypothesis with the hypothesis that tissue uptake of T4 (and of other hormones) occurs spontaneously via the pool of free hormone have been interpreted as supporting the enhanced dissociation hypothesis (5)(6)(7), the results of these studies have all been analyzed with very restrictive assumptions placed on the free hormone transport model (3,4). In the absence of these restrictive assumptions, which presently seem difficult to justify (3,4), the data examined fit both models equally well (3,4).…”