THE HEPATIC TRANSCELLULAR TRANSPORT OF 3,5,3'-TRIIODOTHYRONINE IS REDUCED IN AGED RATS

The mechanisms of age-related reduction in tissue-responsiveness to thyroid hormones is not clear. Since the first step in hormone action is the transport of the hormone from plasma to the tissues, tissue uptake of T3 was determined in three groups of male Fischer 344 rats: young (6 months old), aged (24-26 months old) and young rats pair-fed with aged rats. At steady state, total tissue uptake of T3 in the liver, heart and rectus abdominis muscle was reduced in aged rats while T3 uptake by cerebral tissues, femoris and soleus muscles was not altered with age. The subcellular distribution of T3 in the liver was determined and the binding power of cytosol and plasma was measured by equilibrium dialysis. In vitro saturation techniques provided estimates for the affinity (Ka) and binding capacity for l- and d-T3 of isolated hepatic nuclei at 37°C. The plasma concentration of T3 was determined with radioimmunoassay. From these parameters the free cytosolic to plasma T3 ratio ( Fc Fp) and free nuclear to cytosolic ratio ( Fn Fc) were calculated. The Fc Fp for l-T3 was significantly reduced in aged rats (2.34 ± 0.15) compared to young rats (4.33 ± 0.16) and young rats pair-fed with old (3.55 ± 0.46). The Fc Fp for d-T3 were 6.2 ± 0.39, 24.3 ± 2.3 and 10.1 ± 1.5, respective. The affinity constant (Ka) and the maximum binding capacity measured in isolated hepatic nuclei were not different in the three groups of rats. However, the nuclear uptake of l-T3 ( T3N P: percentage of dose per mg DNA per percentage of dose per ml plasma) was significantly reduced in aged rats (0.29 ± 0.03) and young rats pair-fed with old (0.32 ± 0.02) compared to young rats fed ad libitum (0.44 ± 0.02). The corresponding values of d-T3 were 0.09 ± 0.007, 0.13 ± 0.006 and 0.22 ± 0.01, respectively. The Fn Fc of l- and d-T3 was not altered in aged rats or young rats pair fed with old. The liver uptake index (U1) of l-[125I]T3 was determined in vivo with single injection tissue sampling technique. The liver uptake index in old rats (73.3 ± 9.9%) was significantly reduced compared to young rats (107.5 ± 9.4%). These results indicate that (1) cellular uptake of T3 is reduced in aged rat liver. These changes may be in part secondary to age-related reduction in food intake. (2) Measurements of free hormone concentration gradients across the cellular and nuclear membranes indicate that the age-related deficit in T3 uptake occurs primarily at the plasma membrane level. (3) The disproportionate reduction of cellular uptake of l- and d-T3 suggest that the reduced transport capacity of T3 in aged rats is associated with alterations in stereospecificity of the T3 transport. © 1990.