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  • Author: Masahiro Sugawara x
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Michiyo Nasu and Masahiro Sugawara

Nasu M, Sugawara M. Exogenous free iodotyrosine inhibits iodide transport through the sequential intracellular events. Eur J Endocrinol 1944;130:601–7. ISSN 0804–4643

We describe a new function of exogenous iodotyrosine as a regulator of iodide transport. Porcine thyroid follicles in culture were preincubated with 0–20 μmol/l monoiodotyrosine or diiodotyrosine (DIT) in the presence of bovine thyrotropin (TSH) for 24 h; these iodotyrosines inhibited iodide uptake in a dose–response manner. Extracellular [125I]DIT was actively transported to the thyroid follicle in the presence of TSH or (Bu)2cAMP. Inhibition of iodide uptake by iodotyrosine required preincubation with iodotyrosine in the presence of TSH; without TSH, iodotyrosine was ineffective. Follicles preincubated with DIT for 24 h inhibited TSH-mediated cAMP production, which is an important signal for iodide transport. Inhibition of iodide uptake and cAMP generation by iodotyrosine was negated characteristically by 3-nitro-l-tyrosine, an inhibitor of iodotyrosine deiodinase, or by methimazole, an inhibitor of thyroid peroxidase. Our findings suggest that iodotyrosine regulates iodide transport through the following sequential intracellular events: TSH-dependent iodotyrosine transport into the thyroid cell; deiodination of iodotyrosine and release in iodide; iodine organification by the peroxidase system; inhibition of cAMP generation by organified iodine; and inhibition of iodide transport. Thus, exogenous iodotyrosine can serve as an inhibitor of thyroid hormone formation only when TSH is present

M Sugawara, Wadsworth VA Hospital (11 IM), Wilshire and Sawtelle Blvds, Los Angeles, CA 90073, USA

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Haruhisa Fukayama, Michiyo Nasu, Saburo Murakami and Masahiro Sugawara

We studied the antithyroid action of cigarette smoking products (nicotine, cotinine, and thiocyanate) in the physiological culture system of porcine thyroid follicles. Iodide uptake, iodine organification, de novo thyroid hormone formation, and iodide efflux were measured in the presence of 0–200 μmol/l nicotine, cotinine, or potassium thiocyanate. Nicotine and cotinine did not inhibit iodide transport or thyroid hormone formation. Thiocyanate concentrations equivalent to serum levels of smokers showed three independent antithyroid actions: (i) inhibition of iodide transport, (ii) inhibition of iodine organification, and (iii) increased iodide efflux. Inhibition of iodide transport by thiocyanate was competitive with iodide and independent of TSH concentration. Thiocyanate did not inhibit TSH mediated cAMP production or Na+K+ATPase activity, a sodium pump for iodide transport. When 50 μmol/l thiocyanate was added 2 h after incubation with iodide or when 1 μmol/l thiocyanate was added from the beginning of incubation, iodine organification was inhibited without changing iodide transport. De novo thyroid hormone formation was clearly inhibited by 50 μmol/l thiocyanate. Thiocyanate increased iodide efflux although the degrees of iodide efflux by 10 μmol/l and 100 μmol/l thiocyanate did not differ significantly. In summary, thiocyanate, a product of smoking, has three independent antithyroid activities. The data of iodide transport kinetics suggest that thiocyanate can be an antithyroid agent particularly in iodine deficiency.

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Ge Chen, A Eugene Pekary, Masahiro Sugawara and Jerome M Hershman

Hydrogen peroxide plays an important role in the regulation of iodination and thyroid hormone formation. In the present study, the effect of exogenous H2O2 on 125I transport and organification was investigated in FRTL-5 rat thyroid cells. Less than 20 passages after subcloning, cells in 24-well plates (6 × 104 cells/well) were maintained in a thyrotropin (TSH)-containing medium (6H) for 3 days. A TSH-free medium (5H) was then used for the next 7 days. A 1-h exposure to H2O2 stimulated 125I transport and 125I organification at 0.1–0.5 mmol/l H2O2 and had a toxic effect on FRTL-5 cells at 5 mmol/l. Hydrogen peroxide (0.5 mmol/l) augmented the iodide transport and iodine organification induced by TSH (333U/l) by two- and threefold, respectively. The biphasic effect of H2O2 was blocked totally by 5–200 μg/l of catalase. Catalase by itself did not influence TSH-mediated 125I transport and 125I organification. Hydrogen peroxide (0.5 mmol/l) added to cells in 5H medium increased Na+K+-ATPase activity twofold. Ouabain (1 mmol/l), an inhibitor of Na+K +-ATPase, completely inhibited the twofold increase in 125I transport induced by 0.5 mmol/l H2O2 but only inhibited H2O2-induced 125I organification by 28%. Methimazole (1 mmol/l), an inhibitor of thyroid peroxidase, had no effect on H2O2-mediated 125I transport but totally blocked the fivefold rise in 125I organification induced by 0.5 mmol/1 H2O2. The effect of H2O2 on intracellular cyclic adenosine monophosphate (cAMP) levels also was studied. Hydrogen peroxide (0.5 mmol/l) decreased baseline and 160 mU/l TSH-induced cAMP levels by 35 and 87%, respectively, while a 3-h incubation with 0.5 mmol/l H2O2 increased Na + K +-ATPase in 5H and 6H media. We conclude that H2O2 plays an important role in the regulation of iodide transport and organification and also may affect signal transduction and the electrochemical gradient in thyroid cells. Our results also provide evidence that functional thyroid peroxidase activity is present in FRTL-5 cells.

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Shuji Fukata, Fumio Matsuzuka, Akira Kobayashi, Keisuke Hirai, Kanji Kuma and Masahiro Sugawara

This report describes two unusual cases of subacute thyroiditis from which Graves' disease with hyperthyroidism developed seven to eight years after complete recovery. The first case is a 45-year-old woman who developed hyperthyroidism seven years after recovering from subacute thyroiditis. This patient had a genetic predisposition to both subacute thyroiditis HLA-BW35 and Graves' disease (HLA-BW46). The second case is a 60-year-old woman who developed hyperthyroidism eight years after the episode of subacute thyroiditis; her HLA showed neither BW 35 nor BW 46. It has been reported that if hyperthyroidism is to develop following subacute thyroiditis it occurs within one year. Our observation indicates that it may occur seven or eight years later.

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Xuan-Ping Pang, Jerome M. Hershman, Vierka Smith, A. Eugene Pekary and Masahiro Sugawara

Abstract.

Previous work showed that treatment of rats with tumour necrosis factor-α produced a model of nonthyroid illness in which there was reduction of circulating thyroid hormones and TSH, reduced thyroid response to TSH, and reduced thyroid iodide uptake. In vitro studies showed that tumour necrosis factor-α binds to a specific receptor on FRTL-5 rat thyroid cells, that TSH increases the number of tumour necrosis factor-α receptors, and that tumour necrosis factor-α inhibits iodide uptake by these cells. In the present study, we obtained additional data on the effects of tumour necrosis factor-α on FRTL-5 cells and studied the mechanism of action of tumour necrosis factor-α in these cells. Tumour necrosis factor-α inhibited both basal and TSH-stimulated [125I]iodide uptake; tumour necrosis factor-α slowed the recovery of [125I]iodide trapping after the cells were exposed to TSH and augmented the loss of the [125I]iodide trapping function after the cells were deprived of TSH; tumour necrosis factor-α inhibited [125I]iodide trapping in a noncompetitive manner; tumour necrosis factor-α did not affect cell growth of FRTL-5 cells. Interleukin-1 (IL-1) also inhibited basal and TSH-stimulated [125I]iodide uptake, but it stimulated cell growth. Tumour necrosis factor-α and IL-1 did not affect the generation of cAMP in the presence or absence of TSH; these cytokines blocked the cAMP-induced stimulation of [125I]iodide uptake. Tumour necrosis factor-α did not affect [3H]arachidonic acid uptake or release by FRTL-5 cells. The inhibitors of the phospholipase A2-arachidonic acid pathway did not affect the action of tumour necrosis factor-α. The H2O2 scavenger, catalase, did not block the action of tumour necrosis factor-α. The results show that both tumour necrosis factor-α and IL-1 inhibit FRTL-5 function and that the site of action of these cytokines is distal to the production of cAMP. The actions of tumour necrosis factor-α on FRTL-5 cells do not appear to be mediated by the phospholipase A2-arachidonic acid pathway or by H2O2.

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Jerome M. Hershman, Koonlawee Nademanee, Masahiro Sugawara, A. Eugene Pekary, Richard Ross, Bramah N. Singh and J. J. DiStefano III

Abstract. Cardiac patients taking amiodarone, a potent anti-arrhythmic drug, often have supranormal serum thyroxine (T4) levels and normal or mildly reduced serum triiodothyronine (T3) levels. We studied T4 and T3 kinetics and conversion of T4 to T3 in 5 men with recurrent paroxysmal tachycardia before and after 5–6 weeks of therapy with amiodarone (dose 200–800 mg/day). The patients were also receiving various medicines for cardiac disease. Each was injected with tracer doses of labelled T4 and T3; serum samples were processed by TCA precipitation and ethanol extraction. The data were analyzed with the aid of six-compartment model for T4 and T3 kinetics. Mean total body T3 production rate, total body T3 pool size, and conversion of T4 to T3 were all reduced in patients taking amiodarone.

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Masahiro Sugawara, Dean T. Yamaguchi, Hsin Y. Lee, Kurumi Yanagisawa, Saburo Murakami, Craig N. Summer, Daisy G. Johnson and Seymour R. Levin

Abstract.

This study describes the effects of hydrogen peroxide on the two iodide transport systems, I− influx and I− efflux, in the cultured FRTL-5 rat thyroid cells. I− influx was measured by the amount of I− taken up by the cells during incubation with Na125I and NaI for 7 min, and I− efflux was measured by calculating the rate of 125I release from the 125I-loaded cells in the presence and absence of 5 mmol/l H2O2. Exposure to greater than 100 μmol/l H2O2 for 40 min caused a significant inhibition of I− influx; the inhibition was reversible and non-competitive with iodide. Thyroid Na+K+ATPase activity, a major mechanism to drive I− influx, decreased by 40% after the cells were exposed to 5 mmol/l H2O2 for 10 min. H2O2 enhanced I− efflux only when Ca2+ was present in the medium. The mechanism of an enhanced I− efflux by H2O2 appears to be mediated through the elevation of free cytosolic Ca2+ concentration. Our data indicate that H2O2 can affect I− transport by inhibiting I− influx and enhancing I− efflux.