An Analysis of the Sources and Quantity of 3,5,3′-Triiodothyronine Specifically Bound to Nuclear Receptors in Rat Cerebral Cortex and Cerebellum*

Recent studies have indicated that there is rapid in vivo conversion of L-125IT4 to L-T3 in rat cerebral cortex and cerebellum. These early studies showed significant quantities of 125IT3 specifically bound to nuclear thyroid hormone receptors. The amount of 125IT3 relative to the simultaneously injected 125IT3 in cell nuclei was greater in the cerebral cortex and cerebellum than in other tissues examined, suggesting a major contribution of locally generated T3 to total nuclear T3 in these organs. The present studies have been performed to assess the relative contribution of both T3 sources, the plasma and local 5′-deiodination to the total mass of T3 specifically bound to the nuclear receptors of cerebral cortex and cerebellum in euthyroid rats in steady state conditions. To determine the maximal binding capacity of the nuclear receptors in these two tissues, rats were injected with increasing quantities of unlabeled T3 along with labeled T3. The maximal binding capacity of the nuclear receptors in cerebral cortex was 266 pg T3/mg DNA (95% confidence limits, 242–290) and that for cerebellum was 95 pg T3/mg DNA (89–101). Euthyroid rats were then given 125IT4 and 131IT3 and, after suitable corrections for the contribution of plasma 125IT3 to nuclear 125IT3, they were given the locally generated nuclear 125IT3. Local (Lc) T3(T4), was computed. At 15 h or longer after 125IT4 injection, Lc T3(T4) accounted for more than 80% of the total nuclear 125IT3 in cerebral cortex and approximately 67% of that in the cerebellar nuclei. The nuclear Lc 125IT3(T4) to serum 125IT4 ratio was constant between 15 and 24 h after the injection. The gravimetric amount of nuclear Lc T3(T4) was thus estimated by multiplying this ratio by serum T4 RIA. In addition, the nuclear to serum ratio for T3, at the peak of nuclear 131IT3, and the serum T3 RIA were used to estimate the contribution of plasma T3 to nuclear T3. In the cerebral cortex, nuclear Lc T3(T4) was 195 pg/mg DNA occupying 73% of the maximal binding capacity of these receptors. Plasma T3 contributed 56 pg T3/mg DNA, 21% of the binding capacity, resulting in over 90% occupancy of the nuclear thyroid hormone receptors. For cerebellum, Lc T3(T4) was 30 pg/mg DNA (32% of the maximal binding capacity), whereas plasma T3 contributed about 23 pg/mg DNA or 24% of the maximal binding capacity. The occupancy of cerebellar nuclear thyroid hormone receptors was 56%. These results indicate that T3 generated intracellularly from T4 contributes more than half of the T3 specifically bound to nuclear receptors of cerebral cortex and cerebellum. Furthermore, it appears that these receptors in cerebral cortex are nearly saturated at endogenous serum T3 and T4 concentrations. The results suggest that T4 plays an important role as a source of intracellular T3 in the central nervous system.