Rate Of Deiodination Research Articles

Failure of TSH radioimmunoassay to consistently detect mild TSH mediated thyroid stimulation.

SUMMARYThe sensitivity of the radioimmunoassay for serum TSH has been tested against a direct method for assessment of thyroid function. Fifteen healthy euthyroid volunteers received an oral dose of 80 μCi 125I in order to label endogenously produced thyroid hormones. Five days later 20 μCi 131I‐T4 were injected intravenously to serve as an internal reference source of T4 deiodination rate. The TSH response to an oral dose of 3 mg TRH given on two consecutive days was evaluated by radioimmunoassay and by determination of urinary 125/131I ratios.An increase of the urinary 125/131I ratio of the order of 200% (P<0.01 and P= 0.02) indicated an identical stimulation of the thyroid gland on both days. Following the first dose of TRH the serum TSH the serum TSH level rose by an average of 35% (P<0.05) whereas no change of TSH concentration could be detected on the second day of TRH administration. The findings indicate that mild TSH‐mediated stimulation of the thyroid gland may escape detection by radioimmunoassay of serum TSH concentration. Thus, the sole failure of serum TSH levels to rise by a measurable amount does not at present constitute proof for the autoregulatory nature of an observed change of thyroid function.

Deiodination of 131-I-labeled thyroxine in the fetal rat.

SummaryIn vitro deiodination of 131I-T4 as an index of T4 to T3 conversion, was assessed in homogenates of fetal and adult rat liver and kidney, to explore whether differences existed which might account for the low fetal concentrations of serum T3 observed by others. The deiodination rate per milligram of protein was greater for both kidney and liver homogenates in the fetus than in adult rats. These results suggest that fetal T4 deiodination is not decreased in comparison to the neonatal or adult rat. Thus, the mechanism for the low serum T3 concentration in the fetus does not appear to be a decreased production of T3 from T4, insofar as in vitro T4 deiodination may reflect in vivo T4 to T3 conversion.

Some effects of altitude on thyroid function.

Experiments have been performed to assess the effects of altitude on thyroid function and thyroxine (T4) metabolism. Sprague—Dawley rats were exposed in a hypobaric chamber to a reduced atmospheric pressure equivalent to an altitude of 18,000 feet, for either 3 or 30 days. Thyroid function was determined by measuring the rate of uptake of iodine (127I) by the gland with a double isotope technique, the concentration of T4 in the gland, and the rate of secretion of 125I from the gland prelabeled with the isotope. Peripheral turnover of T4 was measured in animals equilibrated with 131I—T4 by administration of a daily dose of known specific activity; thyroidal accumulation of 131I was prevented with KC104. The results indicate that the activity of the thyroid gland was greatly decreased in both groups of exposed rats; decreases in the rate of uptake of iodine by the gland, the concentration of T4 in the gland and the rate of secretion of iodine by the gland were observed. The rate of deiodination was greatly ...

Propylthiouracil inhibits the conversion of L-thyroxine to L-triiodothyronine. An explanation of the antithyroxine effect of propylthiouracil and evidence supporting the concept that triiodothyronine is the active thyroid hormone.

6-n-propylthiouracil (PTU) administered to male Sprague-Dawley rats maintained on 2 and 5 mug L-thyroxine (T(4))/100 g body weight resulted in a marked reduction in the rate of conversion of L-thyroxine to L-triiodothyronine (T(3)). These effects could not be ascribed to induced hypothyroidism since the group maintained on 5 mug T(4)/day had normal levels of liver mitochondrial alpha glycerophosphate dehydrogenase. In confirmation of previous studies, PTU also reduced the fractional rate of deiodination of T(3). These observations provide a possible explanation of the many published observations indicating that PTU antagonizes the tissue effects of T(4) but not of T(3). The data suggest that monodeiodination of T(4) but not of T(3) is essential before hormonal effects can be manifested at the cellular level.

Deiodination of thyroid hormones by the perfused rat liver.

1. An investigation has been made into the deiodination of thyroid hormones by the perfused rat liver. The hormones were labelled with (125)I in the phenolic ring and the rate of deiodination was estimated by measuring the release of radio-iodide into the perfusate.2. At tracer concentrations, 0.98% of the liver thyroxine is deiodinated/5 min. The deiodination of tri-iodothyronine is considerably faster, 3.3%/5 min.3. Deiodination is very sensitive to changes in temperature.4. The reaction shows saturation kinetics typical of many enzymes, the reciprocal of the rate of deiodination being proportional to the reciprocal of the hormone concentration in the tissue. The maximum rate of deiodination of each hormone is about 1.5 mug/min for a whole liver preparation weighing 16 g.5. Tri-iodothyronine inhibits thyroxine deiodination and vice versa, suggesting that a single enzyme is responsible for both reactions.6. Propyl thiouracil (PTU) at high concentrations inhibits the deiodination of both hormones.7. An abnormally high rate of deiodination is associated with the actual injection of hormone into the preparation. This suggests that only the free (unbound) hormone in the tissue is directly available to the deiodinating enzyme.8. About half of the whole body deiodination of thyroxine is relatively insensitive to PTU. It is suggested that most of this type of deiodination is performed in the liver and that the process is one of inactivation.

Formation of nondissociable hormone-protein complexes during the in vitro incubation of L-thyroxine and 3,5,3'-triiodo-L-thyronine with hepatic microsomes.

Incubation of hepatic microsomes with 3,5,3′-triiodo-L-thyronine or L-thyroxine labeled with 126I in the phenolic ring results in both deiodination and the formation of labeled microsomal iodoprotein which cannot be extracted with ethanol. Chromatography of Na3PO4 hydrolysates of the iodoprotein indicated that at least 20% of the radioactivity was in the form of the labeled hormone used in the incubation. Control studies with 131I-labeled hormone, which was added after completion of the incubation, indicate that the 125I-hormone recovered greatly exceeded that which could be attributed to incomplete extraction of unreacted hormone. In addition to the iodothyxonines, iodide and unidentified peaks which remained near the point of application were identified in the digests of the microsomal iodoprotein. Kinetic studies and studies using chemical inhibitors suggest that the rate of hormone-protein complex formation is proportional to the rate of deiodination. The kinetic studies also militate against the poss...

Thyroxine metabolism and thyroid function in rats following administration of estrogen.

Previous studies from this laboratory indicate that thyroid activity and thyroxine (T4) metabolism are increased in the pregnant rat, and that deiodination of the hormone by the fetuses and changes in T4-binding activity in serum may be contributing factors. The present study is concerned with the role of estrogens in these changes. T4 metabolism was studied in female rats equilibrated with 131I-T4, 2 μg/100 g body wt/day, of known specific activity. Administration of estradiol benzoate (EB), 2.5–25 μg/day, resulted in an increase in the rate of excretion of 131I- in urine and a decrease in serum 131I-T4 concentration, indicating an increase in the rate of T4 deiodination. The effects were most marked during the first 2 days of therapy but were only rarely seen after day 10. As indicated by red blood cell and resin 131I-T4 uptake tests, EB had no effect on the T4-binding activity in serum. EB, 2–5 μg daily for 2 days, resulted in a significant increase in both 131I and stable iodine 127I uptake by the thy...

A new method for the measurement of acute alterations in thyroxine deiodination rate in man.

A newly devised dual labeled iodine isotopic method is described for the detection and quantitation of alterations in thyroxine (T(4)) deiodination rate in man. This method employs the principle of a constant (125)I infusion to serve as a reference source for the generation of (131)I derived from the deiodination of T(4)-(131)I. Measurement of these two iodide isotopes are made in serially timed urine collections and are expressed in terms of a ratio value. Using this technique, it was possible to measure accurately the effects of a single dose of 6-propylthiouracil (6-PTU) in producing inhibition of T(4) deiodination in euthyroid subjects. It was also possible to assess the time of onset, duration of action, and degree of inhibition produced by 6-PTU. Employing single doses of 6-PTU, ranging from 100 to 1000 mg, there was found to be a log dose relationship with a degree of inhibition observed in T(4) deiodination. In control studies T(4) deiodination rate was found to be constant for periods ranging up to 72 hr in normal ambulating subjects. The acute administration of many other agents was employed in an attempt to alter the T(4) deiodination rate. These included diphenylhydantoin, methimazole, triiodothyronine, thyroxine, thyroid stimulating hormone (TSH), adrenocorticotropin (ACTH), hydrocortisone, predinsolone, potassium iodide, epinephrine, and oxytocin. No detectable change in T(4) deiodination rate was observed with these agents in the dosage ranges employed in this study. The lack of any observable alteration in the T(4) deiodination rate in response to this array of drugs and hormones appears to indicate that the availability of T(4) to intracellular sites of deiodination and possibly action is well modulated to resist abrupt changes.

Thyroxine metabolism and thyroid function in the cold-adapted rat.

Thyroid function and thyroxine (T4) metabolism were assessed in rats maintained at 4 or 22 C for at least 3 months. In the coldadapted rat, thyroidal uptake of iodine was increased up to 3-fold. Since total glandular iodine was unchanged, thyroid secretion rate was presumed to be similarly increased. The metabolism of T4 was studied in rats (KC104-treated to prevent 131I uptake by the thyroid) iso topically equilibrated with 131I-T4 of known specific activity. Cold-adapted rats excreted less iodide in urine than did controls, when receiving twice the dose of T4, and not significantly more than controls when given 4 times the dose, although the latter dose raised the serum T4 level above normal. The apparent reduction in the rate of deiodination was not due to changes in the intrinsic deiodinating activity of tissues, or to changes in the T4-binding activity of serum. Total and free T4 levels were not altered. The total turnover of T4 was increased due to a marked increase in the clearance from plasma thro...

Studies of peripheral thyroxine distribution in thyrotoxicosis and hypothyroidism.

Compartmental analysis of the peripheral distribution of labeled thyroxine was applied to various groups of subjects with thyrotoxicosis and hypothyroidism. It was observed that the hepatic incorporation of thyroxine was augmented in subjects with Graves' disease when compared to non-Graves' disease control groups at all levels of thyroid function. Decreased values of hepatic incorporation occurred in primary hypothyroid subjects. These lowered values were not acutely corrected by elevation of the serum thyroxine level, but were observed to be rectified after several months' therapy with exogenous thyroid hormone. These alterations of the hepatic thyroxine-(131)I incorporation were independently verified by direct quantitative liver scintiscan determinations. Employing a dual thyroxine tracer system, we were able to demonstrate that during the early phases of equilibration of a tracer dose of thyroxine, alterations in the rate of deiodination were observed to be present in the various thyroid disease states. Increased deiodination rates were found in subjects with Graves' disease and the reverse was noted in patients with primary hypothyroidism. Kinetic analysis of thyroxine compartmental distribution during this early phase of equilibration of a labeled thyroxine tracer indicated that the primary tissue uptake occurred in the liver. These findings supported the contention that the amount of labeled thyroxine incorporated in the liver may be directly related to the deiodination rate of thyroxine by that organ. The pathogenetic basis of these alterations is presently unknown.

Thyroxine deiodination during cold exposure in the rat.

1. The urinary radio-iodide excretion following injection of [(131)I]thyroxine and tri-iodothyronine is increased in acutely cold-exposed, thyroidectomized rats.2. This cold response is demonstrable in animals which are fed or fasted or deprived of both food and water. Cold exposure does not increase the rate of urinary excretion of a tracer dose of radio-iodide. It is concluded that cold exposure accelerates the rate of deiodination of both thyroxine and tri-iodothyronine.3. It is confirmed that both adrenaline and noradrenaline administered in vivo can enhance the rate of thyroxide deiodination.4. The sympathetic blocking agents guanethidine and bethanidine reduce the extra deiodination of thyroxine induced by cold exposure. Bethanidine was also found to reduce the deiodination of tri-iodothyronine during cold.5. There is a positive correlation between the deiodination of thyroxine and the urinary catecholamine excretion in the cold-exposed but not the warm-exposed rat.6. It is suggested that the enhanced deiodination during cold exposure is mediated by the release of noradrenaline from the sympathetic nervous system.

Thyroxine metabolism and thyroid function in the pregnant rat.

Thyroxine (T4) metabolism and thyroid function were assessed in the pregnant rat. During the last few days of pregnancy, the urinary excretion of 131I, determined in rats isotopically equilibrated with 131I-T4 (0.5-2 Mg/100 g body weight/day), and expressed either in absolute terms or as a percentage of the administered dose, was greatly increased. This indicated an increase not only in the amount, but also in the rate of excretion of iodide derived from T4. The increase was associated with a marked fall in the concentration of T4 in serum. Thus, the clearance of T4 from plasma was greatly enhanced. The increased clearance was due not only to an enhanced rate of deiodination, but also to an increased clearance by the gastrointestinal pathway. After delivery the urinary excretion of iodide was no longer increased and the serum T4 concentration returned to normal within a few days. Studies of T4 metabolism in vitro indicated that, although hepatic deiodinating activity was normal in the 20-day pregnant rat,...

Effect of a malignant tumor on thyroxine metabolism and thyroid function in the rat.

The effects of a malignant tumor (Walker 256) on thyroid hormone economy were assessed. PBI in serum was considerably reduced in tumor-bearing animals. Urinary excretion of 131I in tumorous rats isotopically equilibrated with 131I-labeled T4 (5 μg/day) was significantly greater than in corresponding control animals, indicating that the deiodination of T4 was increased. This increase was associated with a reduction in the concentration of 131I-T4 in serum; thus, the rate of clearance of T4 from plasma was greatly increased in the tumorous rats. This increase was due, not only to the enhanced rate of deiodination, but also to an increased rate of clearance by the gastro-intestinal pathway. The increased rate of clearance was apparently not the result of a primary stimulation of intracellular deiodinating mechanisms; no change in the in vitro deiodination of T4 in tissues of tumorous animals was observed and deiodination by the tumorous tissue itself was minimal. In tumorous animals, increases were noted in ...

The determination of the rate of deiodination of thyroxine in human subjects.

The determination of the rate of deiodination of thyroxine in human subjects.

DISSOCIATION OF THE CALORIGENIC ACTION OF THYROID HORMONES FROM THE DEIODINATION OF L-THYROXINE IN VIVO.

ABSTRACT The rate of deiodination of L-thyroxine was measured in vivo in normal and thyroidectomized rats by a technique of double isotope (125I and 131I) labelling. Small doses of Actinomycin D administered at the same time as 3,5,3′-triiodo-L-thyronine or L-thyroxine almost completely abolished the stimulatory effect of the hormones on basal metabolic rate (B. M. R.) but slightly elevated the rate of deiodination of L-thyroxine. When studied sequentially, the stimulation of B. M. R. preceded the increase in rate of deiodination of the hormone following a single injection of triiodothyronine to thyroidectomized rats. These results suggest that the rate of deiodination is not directly associated with the action of thyroid hormones.

THYROIDAL DEIODINATION DEFECT IN THREE SISTERS WITH SIMPLE GOITER.

Three goitrous sisters showed normal PBI and BMR values, but high 131I uptakes. In all of them thyroid tissue was nearly inactive in deiodination of 131I-labeled L-diiodotyrosine in vitro, while the rate of deiodination of 131I-labeled l-diiodotyrosine administered intravenously was normal. This finding shows that the sisters share defective deiodinating activity of the thyroid, but that the peripheral activity remains intact. The deiodinating activity was found to be defective even after thyroid replacement therapy. The enlargement of thyroid in these cases is probably to be ascribed to the lack of deiodinating activity of the organ. The mating that produced these goitrous sisters was between first cousins. So far as could be ascertained, these sisters were the only goitrous members of the family. This suggests that the defect is due to an autosomal recessive gene which has a sex-controlled tendency in manifestation.

Effect of Feeding Thyroxine on Secretion of I131 in Milk

Summary The metabolism of single doses of NaI 131 was studied in eight comparisons with lactating cows fed 80mg l-thyroxine daily, paired either with their identical twins or with their own performance in adjacent periods when no thyroxine was fed. Two additional cows fed thyroxine and their identical twin controls each received 1 mc I 131 -labelled l-thyroxine. Thyroxine feeding, which began 2 wk before dosing and continued through seven-day collection periods, increased milk production and excretion of I 131 from both the iodide and thyroxine doses in milk, urine, and feces. Orally administered thyroxine increased rate of deiodination and plasma clearance of the thyroxine dose. Although more I 131 from the iodide dose was secreted in milk of thyroxine-fed cows, the concentration of activity per milliliter of milk did not differ significantly from that of controls. Thus, most of the greater excretion of I 131 via the milk when thyroxine was fed was related to higher milk yield.

Defective deiodination of I-131-labeled L-diiodotyrosine in patients with simple goiter.

A study was made of 10 patients with simple goiter and a defect in deiodination of diiodotyrosine. Six patients apparently had a defect both in thyroidal and in peripheral deiodination. All of them had an abnormally slow rate of deiodination of administered I131-labeled Ldiiodotyrosine (l-DIT I131). In vitro studies of the thyroid glands from 3 of these 6 revealed defective deiodination. The other 3 were goitrous cousins of one of them and presumably had a similar defect. The defective deiodination in these 6 patients persisted after thyroid treatment. The other 4 patients had a defect in peripheral deiodination. All of them had an abnormality of deiodination of administered l-DIT I131. Thyroid tissue from 3 of these 4 was tested in vitro, and the deiodinating activity was found to be normal. The fourth was a goitrous daughter of one of them. This defect in peripheral deiodination seemed to be somewhat corrected by thyroid therapy. Observations made on our patients suggest that a defect in deiodination of...

Conditions de formation d'une combinaison rotéique iodée et tritiée au cours de la désiodation des hormones thyroidiennes doublement marquées (131I et 3H)

1.1. Thyroid hormones doubly labeled in α-β position with 3H and in 3′,5′ or 3′ with 131I ([131I, 3H]dl-thyroxine and [131,3H]3,5,3′-triiodo-dl-thyronine) can be deiodinated by mitochondria and several acellular preparations: salt extracts of slices and mitochondria, purified preparations of thyroxine deiodinase. The only labelled compounds produced under the adopted experimental conditions are 131I- and a protein complex, PX, which contains both 3H and 131I. No trittium-labelled thyronine or tyrosine is formed. Since no 3H loss occurs during the incubation there is no exchange between the tritium atoms of the iodothyronine and the hydrogen atoms of the medium, neither do any metabolic modifications occur in the alanine side chain during the process.2.2. The ratio of the specific activities of the two isotopes in the chromatographic zones where residual dl-thyroxine or 3,5,3′-triiodo-dl-thyronine are located is identical to the blank after incubation with thyroxine deiodinase. However, this is not so in the other cases where a disagreement is observed in the rate of deiodination calculated from the measurements of 131I and 3H.PX does always, at the end of the reaction, contain a fraction of the 131I and the total 3H provided for by the disappeared iodothyronine. The 131I concentration of PX is not constant during the incubation period, but decreases when considered as a total and even in relationship to the concentration of 3H. The 131I deiodination of PX takes place in two steps which seems to indicate that the 131I is present in the protein in two different forms.3.3. All the used preparations lead to the same reaction products. Also, it seems that the mechanism of the deiodination is the same in the different cases. The deiodination of the thyroid hormones proceeds in two steps: (a) the fixation of the hormone to the protein, probably the enzyme, (b) the iodine is partially liberated from the complex which retains completely the organic skeleton of the iodothyronine. The formation of PX thus appears as a necessary step in the deiodination of the thyroid hormones.

Deiodination of Thyroxine-131I in Tumour-bearing Rats

The turnover of thyroxine in rats with non-metastatic myeloid leukemia tumor was investigated. The rate of deiodination of thyroxine was determined by administration of a tracer quantity of labeled thyroxine and measuring the amount of inorganic iodide formed by radioactive assay. To ensure complete retention of the iodide formed in the circulation, rats were surgically thyroidectomized 48 hr before the turnover experiment. Tracer thyroxine was injected into the vena cava following a bilateral nephrectomy. Blood samples were collected at 45 min intervals for 5to 8 hr. The serum was separated and the iodine bound to protein and the total serum iodide were deter mined. It was found that the rate of deiodination was higher in animals bearing tumors than in the controls. The animals were killed and the specific activity of the tumors as compared with that of the gastrocnemius muscle. The specific activity of the tumors was 3 to 5times higher than that found in muscle.