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,
ULRICH MERKELBACH,
GERTRAUD STEIGER and
ALBERT G. BURGER
Thyroid Research Unit, Division of Endocrinology Department of Medicine, University of Geneva Geneva, Switzerland
Address all correspondence and requests for reprints to: Dennis Engler, M.D., Thyroid Research Unit, Division of Endocrinology, Department of Medicine, Hopital Cantonal, CH 1211 Geneva 4, Switzerland.
These studies were performed to evaluate the quantitative role of monodeiodination in the peripheral metabolism of T3 and rT3 in man. As a prerequisite step, the serum concentrations of two diiodothyronines (T2s), 3,5-T2 and 3',5' - T2, were established by specific RIAs. In20 normal subjects, mean (±SEM) serum concentrations of 3,5-T2 and 3',5'-T2 were 0.40 ± 0.18 and 2.07 ± 0.13 ng/dl, respectively. The mean concentrations of both T2s were significantly increased in hyperthyroidism. In primary hypothyroidism, the mean 3,5-T2concentration was not significantly different from normal, but 3',5'-T2 concentrations were undetectable in the majority of subjects.
In the first experiments, the MCRs of rT3 and all three T2s were derived by the constant infusion method. Seven normal subjects were infused simultaneously with the three 125I-labeled T2s for 12 h, and in four of the subjects, [131I]rT3 was also administered. The MCRs (liters/day 70 kg; mean ± SEM) were: rT3, 130 ± 17; 3,5-T2, 168 ± 15; 3,3'-T2, 621 ± 84; and 3',5'-T2, 305 ± 45. The daily production rates (PR; micrograms per day/ 70 kg; mean ± SEM) were: rT3, 29.1 ± 1.0; 3,5–T2, 0.6 ± 0.1; 3,3'- T2, 20.8 ±± 4.1; and 3',5'-T2, 5.7 ± 2.1.
In the four subjects who received [131I]rT3, the serum T2 concentrations and PRs were also derived by turnover rate techniques. At equilibrium, 2.0 ± 0.7% and 6.0 ± 1.6% of [131I] rT3 were found as [131I]3,3'-T2 and [131I]3',5'-T2, respectively. The serum T2 concentrations were derived by the product of these percentages and the serum rT3 concentrations and compared with those obtained by T2 RIA. The serum 3',5'-T2 concentration was 1.3 ± 0.4 ng/dl (tracer), and its PR was 3.4 ± 1.1 µg /day (tracer); these values were closely correlated with those obtained by RIA. Serum 3,3'-T2 concentrations were 0.4 ± 0.2 ng/dl (tracer) and 2.7 ± 0.4 ng/dl (RIA), and the PRs were 3.2 ± 1.6 µg/day (tracer) and 20.3 ± 5.7 µg/day (RIA), indicating that rT3 5'-deiodination contributes only a small proportion of serum 3,3'-T2 and its PR. An analysis of the rT3 PR and the 3,3'-T2 and 3',5'-T2 PRs derived from the turnover of rT3 revealed that 28% of the rT3 produced was degraded by monodeiodination. Of this total, 49% of the deiodination occurred at the 5' position and 51% occurred at the 5 position.
In the second group of experiments, the kinetic parameters of T3 were derived by infusing 3,5-[125I]T3 for 36 h in four normal men. The T3 MCR was 36.5 ± 1.6 liters/day 70 kg, and the PR was 40.6 ± 2.1 µg/day. At equilibrium, 0.7 ± 0.1% and 1.5 ± 0.3% of the label were found as [125I]3,5-T2 and [125I]3,3'T2, respectively. The serum concentration of 3,5-T2 was 0.67 ± 0.14 ng/dl (tracer), and its PR was 1.2 ± 0.2 µg/day (tracer); these values were closely correlated with those derived by RIA. Serum 3,3'-T2 concentrations were 1.3 ± 0.2 ng/dl (tracer) and 2.4 ± 0.6 ng/dl (RIA), and the PRs were 8.2 ± 1.3 µg/day (tracer) and 15.1 ± 3.5 µg/day (RIA), again indicating that 3,3'-T2 is mainlyderived from T3 5-deiodination. From a consideration of the T3 PR and the 3,5-T2 and 3,3'-T2 PRs derived from the turnover of T3, it was found that 29% of the daily T3 PR was degraded by monodeiodination. Of this total, 13% of the deiodination occurred at the 5' position, and 87% occurred at the 5 position.
The peripheral turnover kinetics of 3,5-T2 and 3',5'-T2 werealso measured in six patients with untreated primary hypothyroidism. The mean 3,5-T2 MCR and PR were not significantly different from those of the euthyroid population, whereas the mean 3',5'-T2 MCR and PR were significantly decreased compared to the euthyroid values.
From these observations, the following conclusions are derived:1) The three T2s are normally present in human serumand are the products of monodeiodination of T3 and rT3. 2) The concentrations of 3,5-T2 and 3',5'-T2 are significantly increased in hyperthyroidism. 3) In hypothyroidism, 3,5-T2 concentrations are maintained within the normal range by an augmented T3 5' - deiodination. 3',5'-T2 concentrations are generally undetectable in hypothyroidism due to markedly reduced rT3 concentrations and normal rT3 5-deiodination. 4) Monodeiodination per se accounts for 29–56% of the daily disposal of T3 and 28% of the degradation of rT3. 5) 5' - and 5-deiodination contribute equally to the overall monodeiodination of rT3, whereas T3 5-deiodinationis quantitatively much more important than T3 5'-deiodination. 6) Considerations of the total urinary iodide generated from the deiodination of T4 and the contribution to this total derived from the monodeiodination of T3 and rT3 require that the T3s also be degraded by pathways that involve a combination of deiodination and an alteration of the carbon structure of the molecule.
* These studies were presented in part at the 60th Annual Meeting of The Endocrine Society, June 14–16,1978, Miami, FL (Abstract 82) and have appeared in abstract form (Clin Res 27:251A, 1979). This work was supported by Swiss National Foundation Grants 3.925.0.78 and 3.812.0.81.
Supported in part by grants from the Alfred Hospital, Melbourne, and the Ames Co., Australia.
Received May 3, 1983.
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