Slow fractional removal of nonextractable iodine from rat tissue after injection of labeled l-thyroxine and 3,5,3′-triiodo-l-thyronine

Abstract

A B S T R A C T Previous studies have shown that a small but significant proportion of radioiodine from labeled L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (Ts) is incorporated into plasma and tissue proteins and is not, therefore, extractable with ethanol or other organic solvents. Other studies have shown that the complex consists, at least in part, of the iodothyronine in apparent covalent linkage with protein. In the present series of experiments the disappearance rate of nonextractable iodine (NEI) was determined in plasma, liver, and kidney after the injection of rats with a single dose of T4 and Ts labeled with radioiodine in the phenolic ring.The ti of NEI decay was substantially longer than the tj of the initial metabolic removal of T4 (16 hr) and Ts (4-6 hr). Thus, between days 3 and 11 the average tj of plasma NEI derived from T4 was 2.2 days, from T3, 1.9 days; kidney NEI from T4, 7.4 days, from Ts, 6.1 days; hepatic NEI from T4, 4.3 days, from Ts, 5.2 days.The slow disappearance of liver NEI was of special interest in connection with an analysis of previously published data by Tata and associates dealing with the sequential tissue effects after the injection of a single dose of Ts into thyroidectomnized rats. The tj of decay of the various biological effects measured, primarily in the liver, appeared similar to each other, averaging between 4 and 6 days. jected with 25 iyg of T3) was found to be 4.5 days. The coincidence in the slow fractional disappearance rates of hepatic NEI and the dissipation of hormonal tissue effects raises the distinct possibility that T3 interacts with specific cellular receptor sites to form covalent complexes which are slowly removed and serve both to initiate and to perpetuate hormonal action. A mathematical analysis of hormonal reaction mechanisms, based on the assumption of a linearly responsive system, a tA of Ts of 4 hr, and a tj of 4.5 days for the postulated long-lived "messenger" suggests that maximal expression of hormonal activity cannot be attained before 20 hr after the injection of a hormone pulse. This value is broadly consonant with the observed data accumulated by Tata and associates. The existence of a long-lived messenger, possibly a species of NEI, would therefore explain not only the slow dissipation of hormonal effects but also the wellrecognized "lag-time" in the expression of hormonal action.Efforts were also made to define the relationship between extractable and nonextractable radioactivity in the plasma and tissue samples analyzed. The ratio of extractable radioactivity in plasma to extractable radioactivity in tissue became constant shortly after the injection of T8 and T4. The fractional disappearance of extractable radioactivity showed a progressive slowing over the course of the first 10 days after the injection. The distribution of extractable radioactivity between plasma and tissues was compatible with the known partition of exchangeable To and Ts. In the case of Ts, di- 2796The Journal of Clinical Investigation Volume 51 November 1972 ...

Comprehensive Kinetics of Triiodothyronine Production, Distribution, and Metabolism in Blood and Tissue Pools of the Rat Using Optimized Blood-Sampling Protocols*

“…Our mean composite fast pool size is 59 ng. Also, VanArsdel and co-workers (33) and Oppenheimer et al (34) reported nearly identical T3 kinetic responses in liver and kidney to labeled T3 injected iv in the rat, the composite of which closely corresponds to our simulated composite fast pool kinetic response. The kinetic similarity of liver and kidney tissue is also apparent in corresponding results reported for T 4 by the same two groups (33,34).…”

Stimulation of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme by L-triiodothyronine. Characteristics of the response with specific nuclear thyroid hormone binding sites fully saturated.

“…This decay in enzyme proceeds much more slowly than the fall in the plasma and tissue concentrations of T3 which occurs with an average ti of only about 7 h (35). WVlhether the slow decay in the enzyme effect is a reflection of the intrinsic t1 of the a-GPD and MIE molecules or represents the effect of a long-lived rate-limiting intermediate as we have previously suiggested (38) remains an unsettled issue. Recent stuidies in ouir laboratory with a-amantin (39) favor the role of a rate-limiting intermediate.…”

Comparison of the Response Characteristics of Four Lipogenic Enzymes to 3,5,3′-Triiodothyronine Administration: Evidence for Variable Degrees of Amplification of the Nuclear 3,5,3′-Triiodothyronine Signal*

“…This would suggest that the rate of decay of hepatic effects induced by T 3 is not necessarily mediated by the decay of a common rate-limiting intermediate as previously suggested (29,30); neither is the rate of decline limited by T 3 itself, which has a tj of 6-7 h in both liver and plasma (43). Therefore, the possibility should be considered that the decay of each enzyme is limited either by the characteristic decay of the specific mRNA for that enzyme or by the decay of the enzyme itself.…”

“…Although the t$ of disappearance of a-GPD, ME, G-6PD, and 6-PGD did not appear to differ from the t$ range previously observed for ME and a-GPD [2-4 days (22)], the t$ for FAS of 1.4 days was significantly less (P < 0.01) than that of all of the other enzymes tested. In previous studies we had speculated that the fractional decline of all T 3 -induced hepatic effects is limited by a single long lived imprint with a t$ of 3-4 days (29,30). The observation that the decline of FAS is 1.4 days would appear to exclude this possibility.…”