Estimation of thyroxine and triiodothyronine distribution and of the conversion rate of thyroxine to triiodothyronine in man.

Inada, Mitsuo; Kasagi, Kanji; Kurata, Shunichiro; Kazama, Y.; Takayama, Hideo; Torizuka, K; Fukase, M; Soma, Toshiya

doi:10.1172/jci108053

Cited by 120 publications

(44 citation statements)

References 40 publications

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“…It has been suggested that adequate replacement therapy with L-T4 would require doses sufficient to establish values for a serum T4 concentration above the normol range (Sturnick and Lesses, 1961;Lavietes and Epstein, 1964). Moreover, the amount of T3 generated by the conversion of T4 to T3 was found to contribute to approximately 70% of the daily T3 production in normal subjects and, therefore, the 30% of the T3 production was assumed to be secreted directly from the thyroid (Inada et al, 1975). In the present paper, the elevated TSH levels found in 3 patients after T4 administration were reduced to the normal range within 4 weeks after T4 and T3 administration.…”

Section: Discussionsupporting

confidence: 47%

Effect of 3,5,3'L-triiodothyronine administration on serum thyroid hormone levels in hypothyroid patients maintained on constant doses of thyroxine.

et al. 1980

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Section: Discussionsupporting

confidence: 47%

Effect of 3,5,3'L-triiodothyronine administration on serum thyroid hormone levels in hypothyroid patients maintained on constant doses of thyroxine.

et al. 1980

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“…Another correlation between the predictions of these experiments and in vivo data with respect to the effective thyroid status comes from early work by Inada et al (22). These studies showed that in hypothyroid patients, the fractional whole body conversion rate of T 4 to T 3 was 42%, while in the same patients made euthyroid with levothyroxine, this rate fell to 21%.…”

Section: Tablementioning

confidence: 77%

Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans

Maia

Kim²,

Huang³

et al. 2005

Journal of Clinical Investigation

297

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The relative roles of the types 1 and 2 iodothyronine deiodinases (D1 and D2) in extrathyroidal 3,5,3′-triiodothyronine (T 3 ) production in humans are unknown. We calculated the rate of thyroxine (T 4 ) to T 3 conversion by intact cells transiently expressing D1 or D2 at low (2 pM), normal (20 pM), and high (200 pM) free T 4 concentrations. Deiodinase activities were then assayed in cell sonicates. The ratio of T 3 production in cell sonicates (catalytic efficiency) was multiplied by the tissue activities reported in human liver (D1) and skeletal muscle (D2). From these calculations, we predict that in euthyroid humans, D2-generated T 3 is 29 nmol/d, while that of D1-generated T 3 is 15 nmol/d, from these major deiodinase-expressing tissues. The total estimated extrathyroidal T 3 production, 44 nmol/d, is in close agreement with the 40 nmol T 3 /d based on previous kinetic studies. D2-generated T 3 production accounts for approximately 71% of the peripheral T 3 production in hypothyroidism, but D1 for approximately 67% in thyrotoxic patients. We also show that the intracellular D2-generated T 3 has a greater effect on T 3 -dependent gene transcription than that from D1, which indicates that generation of nuclear T 3 is an intrinsic property of the D2 protein. We suggest that impairment of D2-generated T 3 is the major cause of the reduced T 3 production in the euthyroid sick syndrome. IntroductionThe monodeiodination of thyroxine (T 4 ) to 3,5,3′-triiodothyronine (T 3 ) activates the major secretory product of the iodine-sufficient human thyroid gland, producing approximately 80% of the circulating T 3 in humans. The types 1 and 2 iodothyronine deiodinases (D1 and D2) are members of a family of oxidoreductases that catalyze this reaction (1). These integral membrane proteins contain the rare amino acid selenocysteine (encoded by a UGA) in their active site. Both D1 and D2 require an as-yet-unidentified cofactor for the reaction. Several decades ago, D1 was identified in the liver and the kidney of rats and humans, and it is often assumed that this enzyme is the source of most of the plasma T 3 in humans. The more recent discovery of D2 mRNA and activity in human skeletal muscle suggests that D2 could also be a significant source for plasma T 3 production in humans, but this has not been quantitatively defined (1).The biochemical and molecular properties of D2 seem ideal for extrathyroidal T 3 production. Its activity is tightly controlled by the concentration of its preferred substrate, T 4 , since catalysis accelerates the ubiquitination of this enzyme, inactivating it and accelerating its degradation in proteasomes (2). The half-life of D2 in normal cells is 20-30 minutes in the presence of T 4 . The transcription of the type 2 deiodinase (DIO2) gene is also negatively regulated by T 3 (3). In contrast, the D1 protein has a long half-life (>12 hours), and the transcription of the human type 1 deiodinase (DIO1) gene is markedly stimulated by T 3 , just the opposite of what would be expected in a typical feedba...

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“…of 1.21 ± 0.24 1/day and a 98% confidence limit (mean ± 2 S.D.) of 0.73-1.691/day [10,[15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

Thyroxine (T4) Metabolism in an Athyreotic Patient Who Had Taken a Large Amount of T4 at One Time.

et al. 1998

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Abstract. As we had an opportunity to take blood samples from a totally thyroidectomized patient who had attempted suicide by taking 2,000 tg of Levothyroxine (L-T4), the serum levels of thyroid hormones were sequentially measured to investigate the metabolism of circulating thyroid hormones in an athyreotic human. The serum concentrations of most thyroid hormones reached a peak on the second day, but the serum T3 level showed a peak one day later. The maximum concentrations of T4 (315 µg/l), FT4 (48.8 ng/l) and rT3 (0.80 µg/l) were very high, while the peak T3 level (1.92 jug/l) did not exceed the upper limit of the normal range. The serum T4 and rT3 levels returned to their normal range 13-17 days after the suicide attempt. The TSH level was suppressed rapidly and reached its nadir (0.044 mU/I) on the 6th day. During this period, the T112 and MCR of serum T4 were 10.4 days and 0.64 1/day, respectively, which values were almost equivalent to those observed during 15 days after discontinuation of the maintenance L-T4 therapy. In summary, the oral intake of a large amount of L-T4 at one time does not induce a proportional increase in the T3 level in an athyreotic person. The MCR of serum T4 is decreased and the T112 of serum T4 is prolonged, probably due to the lack of intrathyroidal deiodination. These findings support the conclusion that the D1 activity in the thyroid is one of the major determinants in the metabolic clearance of serum T4. Wenzel et al. [5] reported that the maximum concentration of serum T3 after oral intake of an excessive dose (3000 ,ug) of Levothyroxine (L-T4) at one time did not exceed the upper limit of normal range in normal subjects.Nevertheless, the contribution of the thyroid to systemic T4 metabolism is not clear and the precise consequence has not been well documented in reference to the high T3 level in patients with hyperthyroid Graves' disease. In order to evaluate the effect of the thyroid on the metabolism of circulating thyroid hormones, we examined the metabolism of thyroid hormones in an athyreotic patient who had taken an excessive dose of L-T4 at one time.

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Estimation of thyroxine and triiodothyronine distribution and of the conversion rate of thyroxine to triiodothyronine in man.

Cited by 120 publications

References 40 publications

Effect of 3,5,3'L-triiodothyronine administration on serum thyroid hormone levels in hypothyroid patients maintained on constant doses of thyroxine.

Effect of 3,5,3'L-triiodothyronine administration on serum thyroid hormone levels in hypothyroid patients maintained on constant doses of thyroxine.

Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans

Thyroxine (T4) Metabolism in an Athyreotic Patient Who Had Taken a Large Amount of T4 at One Time.

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