Peripheral Metabolism Of Thyroxine Research Articles

Thyroid status and hepatic thyroxine deiodinating activity under high-dose long-term nitrendipine.

The influence of high doses of oral nitrendipine on the hypophyseal-thyroid axis and on peripheral thyroxine metabolism was studied in baboons. Administration of 320 mg oral nitrendipine per kg body weight (b.wt.) for three months caused a hypothyroid state with decreased values for thyroxine and reverse triiodothyronine, elevated TSH, but unchanged triiodothyronine; the lower doses investigated (24 and 48 mg/kg b.wt.) were without any effect. High doses of nitrendipine concomitantly increased hepatic 5'-deiodinating activity by a rise in Vmax, which could be attributed to an increase in the deiodinating enzyme content. Normal T3 serum levels in the presence of low T4 serum concentrations under high dose nitrendipine can be ascribed, at least in part, to the enhanced peripheral 5'-deiodination.

Synthesis and effects on peripheral thyroid hormone conversion of (R)-4-hydroxypropranolol, a main metabolite of (R)-propranolol

The inhibiting effect of (R,S)-propranolol on peripheral T4/T3 conversion can be related to the (R)-isomer. The intention of this study is to clarify if (R)-4-hydroxypropranolol, a main metabolite of (R)-propranolol, develops the same or even a stronger effect on peripheral thyroxine metabolism as the parent drug. (R)-4-hydroxypropranolol was synthesized via (R)-4-methoxypropranolol and their optical purity was checked chromatographically. Twenty patients suffering from hyperthyroidism were divided into five groups and treated with (R)-4-hydroxypropranolol · HCl in dosages from 12 to 75 mg per day in a placebo controlled study over a period of 5 days. The serum hormone levels and resting pulse rate were measured. No significant changes of thyroid parameter could be observed but a significant decrease of resting pulse rate under treatment with 75 mg (R)-4-hydroxypropranolol occurred. It could be concluded that (R)-4-hydroxypropranolol possesses negative chronotropic effects but develops no changes in thyroid hormone metabolism in hyperthyroid patients.

Increased thyroxine turnover after 3,3′,4,4′,5,5′-hexabromobiphenyl injection and lack of effect on peripheral triiodothyronine production

Juvenile male Wistar rats were injected i.p. with 0, 20, or 40 mg/kg 3,3',4,4',5,5'-hexabromobiphenyl and blood samples collected periodically up to 28 days. A dose-dependent depression of the serum thyroxine level was detected, while the circulating triiodothyronine concentration was not affected by the biphenyl congener. Thyroxine turnover in vivo 7 days after injection of the 20 mg/kg dose revealed significant increases of various clearance parameters relative to controls. The fractional clearance rate (day-1) increased by 84%, the daily metabolic clearance rate (mL.kg-1.day-1) increased by 128%, and the daily thyroxine disposal rate (ng.kg-1.day-1) increased by 41%. Also, the thyroxine distribution space (mL/kg) increased by 21%. These results indicated greater thyroxine binding in major organs as well as a marked increase in the peripheral metabolism of thyroxine. The increased thyroxine metabolism is explained by a 4.8-fold induction of uridine 5'-diphosphoglucuronyltransferase activity in liver microsomes. The type I 5'-deiodinase activity in liver homogenates and endogenous concentrations of the cofactor for this reaction, glutathione, were not affected by the biphenyl. This result means that homeostatic mechanisms involving thyroxine conversion to triiodothyronine do not explain the maintenance of serum T3 under these conditions.

Influence of Chronic Treatment with Iopanoic Acid on Thyroxine Metabolism in the Newborn Rat

Parameters of the peripheral metabolism of thyroxine (T4) were studied in the early postnatal period. Iopanoic acid (IOP) was administered to newborn rats that were either euthyroid or rendered hypothyroid in utero by propylthiouracil (PTU) or methimazole (MMI) administration to the mothers during gestation and injected with thyroxine on postnatal days 6 and 7. In euthyroid newborn rats given IOP from postnatal day 6, the plasma T4 level increased (+50%) while the plasma 3,3',5'-triiodothyronine (T3) level slightly decreased (-18%). Peripheral deiodination of T4 was also reduced (about -50%) as estimated by thyroid 125I uptake after injection of 125I (3'-5')L-T4. In the newborn rats rendered hypothyroid in utero and given T4 on postnatal days 6 and 7, IOP treatment started on day 4 decreased the constant rate of elimination (-50%), the distribution volume (-43%) and the metabolic clearance (-74%) of plasma T4. The results were the same in PTU- and MMI-treated newborn rats. The differences between newborn and adult animals under IOP treatment are discussed.

The effects of xenobiotics on the structure and function of thyroid follicular and C-cells.

The mammalian thyroid gland is composed of 2 distinct endocrine cell populations concerned with the synthesis of 2 different classes of hormones. Follicular cells secrete the metabolically active iodothyronines whereas the C-(parafollicular) cells are concerned with the production of calcitonin, a hormone that influences blood levels of calcium and phosphorus, and bone cell metabolism. The synthesis of metabolic thyroid hormones is different than in other endocrine glands because the final assembly of hormone occurs within the follicular lumen. This extracellular synthesis of thyroid hormones is made possible by thyroglobulin, a glycoprotein synthesized by follicular cells. The secretion of thyroid hormones under the influence of pituitary thyrotrophin (TSH) from stores in the luminal colloid is initiated by elongation of microvilli and formation of pseudopods. FD&C Red No. 3 is a tetraiodinated derivative of fluorescein which in lifetime studies increases the incidence of thyroid follicular cell adenomas in male Sprague-Dawley rats. The striking changes in circulating levels of thyroid hormones and morphologic evidence of follicular cell stimulation are the result of alterations in the peripheral metabolism of thyroxine. An inhibition by FD&C Red No. 3 of 5'-deiodinase in the liver and kidney would explain the lower serum triiodothyronine (T3) levels. The pituitary, sensing the lowered circulating levels of T3, increased the secretion of thyroid stimulating hormone which resulted in the morphologic evidence of follicular cell stimulation in the long-term studies. Other xenobiotics increase the incidence of thyroid tumors in rodents by a direct effect on the thyroid gland to disrupt 1 of 3 or more possible steps in the biosynthesis of thyroid hormones. Physiologic perturbations alone, such as iodine deficiency or partial thyroidectomy, can disrupt thyroid hormone economy in rodents and, if sustained, increase the development of thyroid tumors. The wide variety of drugs, chemicals, and physiologic perturbations which increase thyroid tumor development appear to act through a secondary (indirect) mechanism to promote tumor development by causing a long-standing hypersecretion of thyroid stimulating hormone. Nodular and/or diffuse hyperplasia of C-cells occurs with advancing age in many strains of laboratory rats and in response to long-term hypercalcemia in certain animal species and human beings. Focal or diffuse hyperplasia often precedes the development of C-cell neoplasms. Radiation and the feeding of diets high in vitamin D resulting in hypercalcemia have been reported to increase the incidence of C-cell tumors in rats.

Studies on the mode of action for thyroid gland tumor promotion in rats by phenobarbital

A study was conducted to determine the mode of action for phenobarbital promotion of thyroid follicular cell neoplasia in rats using an initiation-promotion model established by Hiasa et al. (Y. Hiasa, Y. Kitahori, M. Ohshima, T. Fujita, T. Yuasa, N. Konishi, and A. Miyashiro, 1982a , Carcinogenesis 3, 1187–1190). Seven groups of Charles River Crl: CD(SD)BR rats (20/sex/group) were treated with either saline or 700 mg/kg DHPN [ N-bis(2-hydroxypropyl)nitrosamine] administered subcutaneously once a week for 5 weeks (Initiation Phase) followed by 15 weeks of treatment with control diet or diets containing 500 ppm of phenobarbital (Promotion Phase). Groups of rats were also treated with l-thyroxine (50 μg/kg/day) in the diet to determine its effect on thyroid gland tumor promotion by phenobarbital. The incidence of thyroid follicular adenomas in DHPN male rats treated with phenobarbital was markedly increased [83% ( 15 18 rats)] as compared to rats receiving DHPN alone [37% ( 6 16 rats)]. Thyroxine treatment completely blocked the tumor promoting effect of phenobarbital in that the tumor incidence [25% ( 5 20 rats)] was reduced back to or somewhat less than that observed with DHPN alone. In female rats no tumors were observed with DHPN nor was a promoting effect of phenobarbital observed. These results demonstrate the potential for a microsomal enzyme inducer such as phenobarbital to alter the incidence of thyroid gland neoplasia in the male rat. The inhibitory effect of l-thyroxine on tumor promotion by phenobarbital supports the hypothesis that the promoting effect of phenobarbital is mediated via increased pituitary secretion of thyroid stimulating hormone as a compensatory response to the known effects of phenobarbital on peripheral thyroxine metabolism and excretion.

Peripheral metabolism of thyroxine.

The new edition of Werner's The Thyroid is so massive a monograph that anyone might be forgiven for supposing that all must now be light as regards the thyroid and its hormones. Such a conclusion would be much in error: many important areas remain most murky. Some of the problems involved in understanding the metabolism of thyroid hormones at the cellular level received a recent airing in the lecture of Professor Reed Larsen at the 1987 meeting of the British Endocrine Societies (Larsen, 1987). Although it is now generally accepted that the important thyroid hormone for the cells is tri-iodothyronine (T3), it is not clear precisely how the supply is matched to the cellular need, for T3 forms only a small proportion of the thyroid secretion, the predominant hormone secreted being thyroxine (T4). The cellular supply of T3 depends largely on conversion of T4 to T3 by an enzyme

Thyroid function tests in thyroid and nonthyroid disease.

Modern day evaluation of thyroid disorders requires a combination of accurate clinical judgement and reliable, sensitive, and specific thyroid functions tests. Principle among the latter are thyroxine (T4) 3, 5, 3'-triiodothyronine (T3), and thyroid-stimulating hormone (TSH). Also playing an important role in special situations are free thyroxine, an assessment of bound and unbound thyroid-binding globulin, TRH stimulation, long-acting thyroid stimulator (LATS), antibodies to thyroid hormone and to thyroid receptors. Basic to interpretation of these tests in the clinical setting is a comprehension of the relationship of the hypothalamus, the pituitary, and the thyroid gland as well as a knowledge of the peripheral metabolism of thyroxine and triiodothyronine. The role of each of these laboratory tests in the evaluation of hyper- and hypometabolic states, their alteration in nonthyroid and other endocrine disorders, and the effects of environmental and physiological factors on these tests are reviewed.

The effects of oral cholecystographic contrast agents on thyroid function tests

Iopanoic acid (Telepaque) and sodium iopodate (Biloptin), two contrast agents commonly used for oral cholecystography, have been shown to reduce the serum concentration of triiodothyronine (T3) and increase that of reverse-triiodothyronine (rT3) by altering the peripheral metabolism of thyroxine (T4). This study reports the changes in serum TSH and thyroid hormones in over 30 patients undergoing routine oral cholecystography. Blood was sampled just before ingesting contrast and on 3 other occasions during the following 3 wk. Preliminary data show reduction of serum T3 > 30% below basal levels (p = 0.01) on day 3,4 or 5, with a concomitant increase in rT3 to >200% above basal levels (p = 0.01). Serum T4 showed slight but TSH marked increase. Concentrations of all hormones returned to basal levels by the third week. Consequently, thyroid function tests performed within 3 wk of ingesting these agents should be interpreted with caution. Iopanoic acid (Telepaque) and sodium iopodate (Biloptin), two contrast agents commonly used for oral cholecystography, have been shown to reduce the serum concentration of triiodothyronine (T3) and increase that of reverse-triiodothyronine (rT3) by altering the peripheral metabolism of thyroxine (T4). This study reports the changes in serum TSH and thyroid hormones in over 30 patients undergoing routine oral cholecystography. Blood was sampled just before ingesting contrast and on 3 other occasions during the following 3 wk. Preliminary data show reduction of serum T3 > 30% below basal levels (p = 0.01) on day 3,4 or 5, with a concomitant increase in rT3 to >200% above basal levels (p = 0.01). Serum T4 showed slight but TSH marked increase. Concentrations of all hormones returned to basal levels by the third week. Consequently, thyroid function tests performed within 3 wk of ingesting these agents should be interpreted with caution.

Effect of ethanol on the peripheral metabolism of thyroxine.

To determine the effect of ethanol on peripheral metabolism of T4, deiodinative clearance of T4 and serum concentration of T4, T3 and rT3 were measured in rats isotopically equilibrated with T4. Ethanol 8 g/Kg weight/day was given for 3 days to fasted rats and the results were compared with those normally fed or totally fasted animals. In fasted rats, deiodinative clearance of T4 and serum T4 and T3 concentration, and T3/T4 ratio, were decreased significantly, while serum rT3 concentration and serum rT3/T4 ratio was increased significantly when compared to those in normal rats. When ethanol was administered to fasted rats, deiodinative clearance of T4, serum T4 and T3 concentration and serum T3/T4 returned to normal level while serum rT3 concentration and rT3/T4 ratio remained at higher levels than in normally fed animals. These results could not be interpreted on the basis of shift of 5 monodeiodinase to 5' form or vise versa, and imply that the two deionative process may be independent each other.

Fine Structural Alterations in Thyroid Follicular Cells (FC) and Changes in Serum Thyroxine Produced by Feeding Polychlorinated Biphenyl (PCB) to Rats

The widespread contamination of the environment with PCB, a compound used extensively by industry in hydraulic and heat transfer fluids as well as plasticizers and solvents in adhesives and sealants, has resulted in detectable tissue levels in a large portion of the human population, domestic animals, and wildlife. Intoxication with PCB produces severe hepatic necrosis, degeneration of lymphoid tissues and kidney, skin lesions, decreased reproductive performance, reduced feed efficiency, and decreased weight gain. PCB also has been reported to reduce the binding of thyroid hormone to serum proteins and enhance the peripheral metabolism of thyroxine with increased excretion of thyroxine-glucuronide in the bile (Bastomsky, Endocrinology 95: 1150-1155, 1974).The objectives of this investigation were (1) to investigate the histopathologic, histochemical, and ultrastructural changes in thyroid FC produced by the acute (4 week) and chronic (12 week) administration of low (50 ppm) and high (500 ppm) doses of PCB to rats, (2) to correlate these alterations to changes in serum immunoreactive thyroxine concentration, and (3) to investigate the persistence of the effects of PCB on the thyroid gland.

Diversion of peripheral thyroxine metabolism from activating to inactivating pathways during complete fasting.

In 9 euthyroid obese volunteers, as previously reported, 4 weeks of total caloric deprivation resulted in a striking decrease in serum 3,5;3'-triiodothyronine (T3) concentration. The present studies reveal that this decrease in serum T3 is accompanied by a proportionately similar increase in the serum concentration of 3,3',5' -T3 (reverse T3; rT3). In four additional obese volunteers given suppressive doses of sodium-Lthyroxine (T4) for 1 month prior to fasting, serum T3 concentration declined sharply during a 6-11 day period of fast, while rT3 concentration increased strikingly. Concentrations of both T3 and rT3 returned to control values during a 5 day period of refeeding. The findings indicate that caloric deprivation results in an alteration in peripheral T4 metabolism away from generation of T3 and toward the generation of rT3. Since the former is more active than T4, and the latter is essentially inactive, caloric deprivation appears to shunt peripheral T4 metabolism from activating to inactivating pathways.

The effect of food deprivation of the peripheral metabolism of thyroxine in rats.

Starvation depresses thyroid gland function. In addition, the peripheral turnover of thyroxine (T4) is reduced, in part due to decreased fecal elimination of T4. The present studies were performed to determine if starvation also affects the deiodinative pathway for T4 degradation. Rats were isotopically equilibrated with daily injections of exogenous [131-I]T4 while endogenous thyroidal T4 secretion and concentration of iodide were blocked with KCl04. Following a period of equilibration, either complete or 50% food deprivation was imposed on half the animals. Within 48 h of starvation, the serum T4 concentration of the fully starved rats doubled and remained high throughout. A marked decrease in fecal excretion of T4 was partially responsible for the increase. In spite of variability in the quantity of urinary 131-I excreted, the dieodinative clearance was consistently reduced. These effects were readily reversible upon resumption of normal feeding. Similar though less severe changes were observed in the half-fed rats. In both fully and partially-starved animals, the decreased dieodinative clearance in the face of increased serum T4 levels indicates a significant impairment of peripheral deiodination by some as yet unknown mechanism. In contrast, normal rats equilibrated with doses of T4 sufficient to increase serum T4 levels exhibit increased urinary clearance of iodide derived from T4. Thus the increased serum T4 levels are a consequence of impairment of the deiodinative pathway by starvation as well as decreased fecal T4 excretion. Clearly, voluntary alterations in food consumption must be controlled for differences between groups during experimental studies of T4 utilization.

Effect of physical training on the metabolism of thyroid hormones in man.

The effect of a 6-wk program of physical training (track running) on the peripheral metabolism of thyroxine (T4) and triiodothyronine (T3) was evaluated in a group of 11 men. Measurements were made of hormone turnover, urinay and fecal clearances, plasma hormone concentrations, and hormone binding by plasma proteins in all subjects before and after training, After training, metabolic clearance of T3 was increased 8.5% above the pretraining level due to an increased deiodinative clearance of this hormone. No significant change was observed in plasma T3 concentration. The absolute degradation of T3 increased 10.3% after training. In contrast, no significant change in the metabolic clearance of T4 was detected. Significantly decreased plasma concentration of total T4 after 4 and 6 wk of training was apparently not due to decreased hormone binding by plasma protein since no significant alteration in the dialyzable fraction of T4 was detected. The absolute degradation rate of T4 was decreased 8.8% after training. Possible implications of the observed differential impact of training on the degradation of T4 and T3 regarding thyroid hormone economy are discussed.

Stimulation of the peripheral metabolism of L-thyroxine and and 3,5,3'-L-triiodothyronine in the physically trained rat.

The effect of physical training on the peripheral metabolism of thyroxine and triiodothyronine was evaluated in rats trained on a motorized treadmill for 12 weeks. The metabolism of thyroid hormones was assessed by analysis of plasma disappearance kinetics and hepatic accumulation of injected labeled iodothyronines. Training was associated with increased metabolic clearances of the two hormones. The enhanced hormonal disposition was manifest in increased fecal clearances. Increments of lesser magnitude observed in the urinary clearances of both hormones were not significant. Analysis of the plasma protein and cellular determinants of hormonal turnover, as proposed by Oppenheimer (J Clin Invest 49: 1016, 1970), suggested that the increased hormonal degradation was attributable to stimulation of cellular turnover. The detection of increased hepatic uptakeof iodothyronines provided additional evidence of augmented cellular disposition. These current data extend observations in earlier studies in the rat and ...

Effect of propranolol on various aspects of thyroid function in the rat

The daily administration of propranolol (5–20 mg/kg) to the intact male rat does not effect the serum thyroxine concentration or the peripheral metabolism of 131I-labeled thyroxine. Except for a small decrease in 131I-labeled triiodothyronine, propranolol did not effect the intrathyroidal metabolism of 131I. These findings further suggest that the efficacious use of propranolol in the treatment of many of the signs and symptoms of thyrotoxicosis may not be associated with alterations in thyroid gland function or in the peripheral metabolism of thyroxine.

Thyroxine transport and metabolism in methadone and heroin addicts.

The chronic use of methadone or heroin results in various abnormalities in the transport and peripheral metabolism of thyroxine (T4). An increase in the thyroxine-binding capacity of the thyroxine-binding globulin and in the serum concentrations of T4 and triiodothyronine (T3) may be found in methadone and heroin addicts. In the heroin addicts these changes are accompanied by a decrease in the fractional turnover rate of T4; in patients receiving methadone the turnover rate is normal. Despite these abnormalities, serum free T4 concentrations and total T4 degradation rates were within the normal range of values, and the patients were clinically euthyroid. The causes of these changes remain obscure, probably because of the multiple effects these drugs have on various physiological processes.

The response of the thyroid gland and thyroid hormone metabolism to infectious disease.

A review is presented of the current state of knowledge of responses of the hypothalamic-pituitary-thyroid axis and peripheral thyroxine metabolism to infectious disease. The effects of various infect

Thyroxine kinetics during prolonged estrogen administration.

ABSTRACT The peripheral metabolism of thyroxine (T4) was studied in 13 patients with carcinoma of the prostate receiving estrogen treatment for at least a year, to ascertain whether changes in T4 degradation had occurred. The control group was composed of 8 healthy men of age and weight comparable to that in patients with prostatic carcinoma. In 6 patients with this same disease, short-term paired studies were carried out before and 3 to 6 weeks following estrogen administration. The 13 estrogen-treated patients had a mean daily T4 degradation rate of 80.5 μg, a value significantly lower (p < 0.02) than that in the normal group. The 24-hr thyroidal 131I uptake in the group receiving chronic treatment was similarly decreased as compared to the euthyroid subjects (p < 0.05). None of the patients with prostatic carcinoma evidenced frank clinical manifestations of hypothyroidism. The 6 untreated patients with carcinoma of the prostate had values of T4 degradation similar to those of the normal group. Subseque...

Effects of replacement doses of sodium L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man.

Studies of the effect of L-thyroxine administration (0.3 mg daily for 7-9 wk) on the peripheral metabolism of (131)I-labeled triiodothyronine (T(3)) and (125)I-labeled thyroxine (T(4)) and on the concentration and binding of T(4) and T(3) in serum were carried out in 11 euthyroid female subjects. Administration of L-thyroxine led to consistent increases in serum T(3) concentration (137 vs. 197 ng/100 ml), T(3) distribution space (39.3 vs. 51.7 liters), T(3) clearance rate (22.9 vs. 30.6 liters/day) and absolute T(3) disposal rate (30 vs. 58 mug/day), but no change in apparent fractional turnover rate (60.3 vs. 60.6%/day). The proportion and absolute concentration of free T(3) also increased during L-thyroxine administration. Increases in serum total T(4) concentration (7.3 vs. 12.8 mug/100 ml) and in both the proportion and absolute concentration of free thyroxine also occurred. In five of the subjects, the kinetics of peripheral T(4) turnover were simultaneously determined and a consistent increase in fractional turnover rate (9.7 vs. 14.2%/day), clearance rate (0.84 vs. 1.37 liters/day), and absolute disposal rate (64.2 vs. 185.0 mug/day) occurred during L-thyroxine administration. Despite these increases in the serum concentration and daily disposal rate of both T(4) and T(3), the patients were not clinically thyrotoxic. However, basal metabolic rate (BMR) values were marginally elevated and, as in frank thyrotoxicosis, T(4)-binding capacities of thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) reduced, suggesting that subclinical thyrotoxicosis was present. Thus, the often recommended replacement dose of 0.3 mg L-thyroxine daily may be greater than that required to achieve the euthyroid state. The studies have also provided additional evidence of the peripheral conversion of T(4) to T(3) in man and have permitted the calculation that approximately one-third of exogenously administered T(4) underwent deiodination to form T(3). To the extent that a similar fractional conversion occurs in the normal state, it can be calculated that a major fraction of the T(3) in serum derives from the peripheral deiodination of T(4) and that only a lesser fraction derives from direct secretion by the thyroid gland.