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Alessandro Marsili, Edith Sanchez, Praful Singru, John W Harney, Ann Marie Zavacki, Ronald M Lechan and P R Larsen

T 4 to T 3 by the type 2 deiodinase (D2) is required for suppression of TSH at the pituitary level ( Larsen et al . 1979 ). The requisite degree of saturation of the thyrotroph nuclear T 3 receptors requires both circulating T 3 and D2-mediated

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A Boelen, J Kwakkel, X G Vos, W M Wiersinga and E Fliers

Introduction During fasting, profound changes occur in the hypothalamic part of the hypothalamic–pituitary–thyroid axis (HPT axis), i.e. increased type 2 deiodinase (D2) activity in the arcuate nucleus (ARC) ( Diano et al. 1998

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B Anguiano, R Rojas-Huidobro, G Delgado and C Aceves

reported that the lactating rat mammary gland exhibits type 1 deiodinase (Dio1) which catalyzes the T4 to T3 conversion. This enzyme can be detected beginning in mid-pregnancy, and its synthesis increases considerably 48 h postpartum. In mid

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CH Verhoelst, S Van Der Geyten and VM Darras

Iodothyronine deiodinase in vitro activity studies in the chicken showed the presence of type I and type III iodothyronine deiodinase activity in both liver and kidney. Due to the lack of a specific antiserum the cellular localization of the deiodinase proteins could not be revealed until now. In the present study, specific antisera were used to study the renal and hepatic distribution of type I and type III iodothyronine deiodinase protein in the chicken. Immunocytochemical staining of liver tissue led to an immunopositive signal in the hepatocytes in general. Moreover, a zonal distribution could be detected for both enzymes. Maximum protein expression was shown in a thin layer of hepatocytes bordering the blood veins. Although pericentral localization of type I deiodinase protein has been previously reported in the rat, no data were given concerning type III deiodinase protein. In the present study, we report the co-localization of both enzymes in the chicken. Co-expression of the deiodinases was also found in the kidney. Expression of both proteins was associated with the tubular epithelial cells and with the transitional epithelium, and the inner longitudinal and outer circular muscle layers of the ureter. No staining could be detected in the lamina propria or in the fat tissue surrounding the ureter.

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TG Frankenfeld, VM Correa Da Costa, CC Nascimento-Saba, TM Ortiga-Carvalho, RM Santos, PC Lisboa, DP Carvalho and D Rosenthal

Some authors have reported increased serum thyrotrophin (TSH) in animals chronically treated with lithium, suggesting that lithium might decrease pituitary thyroxine (T(4))-5'-deiodinase activity. On the other hand, the effect of lithium treatment on thyroidal T(4)-5'-deiodinase activity is also unknown. The present study was undertaken to evaluate the effects of lithium treatment on pituitary and thyroid T(4)-5'-deiodinase activity. Serum and pituitary TSH levels and thyroidal and pituitary T(4)-5'-deiodinase activities were determined in 3-month-old isogenic male Dutch-Miranda rats treated with lithium for 8 weeks. Chronic lithium treatment produced a slight increase in pituitary TSH content, but no change in serum TSH, and a significant increase in the thyroidal T(4)-5'-deiodinase activity. However, the pituitary T(4)-5'-deiodinase activity was unaffected by lithium administration. As far as we know, the present data show for the first time that chronic lithium treatment can increase the thyroxine to tri-iodothyronine conversion in the murine thyroid gland, be it directly or indirectly.

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JC Solis-S, P Villalobos, A Orozco and C Valverde-R

The initial characterization of a thyroid iodotyrosine dehalogenase (tDh), which deiodinates mono-iodotyrosine and di-iodotyrosine, was made almost 50 years ago, but little is known about its catalytic and kinetic properties. A distinct group of dehalogenases, the so-called iodothyronine deiodinases (IDs), that specifically remove iodine atoms from iodothyronines were subsequently discovered and have been extensively characterized. Iodothyronine deiodinase type 1 (ID1) is highly expressed in the rat thyroid gland, but the co-expression in this tissue of the two different dehalogenating enzymes has not yet been clearly defined. This work compares and contrasts the kinetic properties of tDh and ID1 in the rat thyroid gland. Differential affinities for substrates, cofactors and inhibitors distinguish the two activities, and a reaction mechanism for tDh is proposed. The results reported here support the view that the rat thyroid gland has a distinctive set of dehalogenases specialized in iodine metabolism.

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J Kwakkel, W M Wiersinga and A Boelen

characteristic decrease of liver 5′-deiodinase type 1 (D1) mRNA expression and activity during illness, which contributes to the diminished serum T3 levels. ( Boelen et al. 1995 , 1996 , Wiersinga 2005 , Jakobs et al. 2002 ). D1 mRNA expression in

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A Baur, K Bauer, H Jarry and J Kohrle

Cytokines are locally produced in the anterior pituitary and act through para-/autocrine mechanisms to modulate cell growth and hormone production. 5'-Deiodinases type I (D1) and type II (D2) are also expressed in the anterior pituitary and play an integrative role in the regulation of hormone production and pituitary feedback. D1 activity is known to be regulated by proinflammatory cytokines in liver and thyroid. Therefore, we examined the effects of IL-1 beta, IL-6 and TNF alpha on 5'-deiodinase activities in reaggregates of rat anterior pituitaries and rat somatomammotroph GH3 cells cultured alone, or in a bicameral culture system together with the murine folliculo-stellate (FS) cell line TtT/Gf. In reaggregate cultures of rat anterior pituitaries IL-1 beta stimulated D1 and D2 dose-dependently and D2 activity was increased by TNF alpha. When GH3 cells were cocultured with TtT/Gf cells, D2 activities were 2.3-fold lower than in GH3 cells cultured alone. TNF alpha (50 ng/ml) and IL-6 (100 U/ml) stimulated D2 in GH3 cells when the cells were cultured alone and treated with these cytokines for 24 h. When TtT/Gf cells in the coculture model were treated with IL-1 beta, TNF alpha and IL-6, no effect on D1 or D2 activities in GH3 cells was observed. In male, adult rats a single LPS injection (i.p.) stimulated D2 and D1 activities in the anterior pituitary, and decreased liver D1 activities and serum TSH levels. In vitro, LPS stimulation of the coculture model of GH3 and FS cells also increased D1 activity. Electrophoretic mobility shift assays (EMSAs) revealed that IL-1 beta and TNF alpha activate the transcription factor NF kappa B in reaggregates of rat anterior pituitaries and in TtT/Gf cells cultured alone or cocultured with GH3 cells. Taken together, these findings imply that in anterior pituitary cells 5'-deiodinase activities are stimulated by locally produced cytokines in a para-/autocrine manner but cell types other than FS cells seem to mediate some of the effects.

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SM van der Heide, BJ Joosten, ME Everts and PH Klaren

We have investigated the hypothesis that uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs) and beta-glucuronidase are jointly involved in a mechanism for the storage and mobilization of iodothyronine metabolites in liver, kidney, heart and brain. Specifically, we predicted UGT activities to decrease and increase respectively, and beta-glucuronidase activity to increase and decrease respectively in hypo- and hyperthyroidism. To this end we have studied the effects of thyroid status on the activities of different enzymes involved in thyroid hormone metabolism in liver, kidney, heart and brain from adult rats with experimentally induced hypo- and hyperthyroidism. We used whole organ homogenates to determine the specific enzyme activities of phenol- and androsteron-UGT, beta-glucuronidase, as well as iodothyronine deiodinase types I and II. Deiodinase type I activities in liver and kidney were decreased in hypothyroid animals and, in liver only, increased in hyperthyroidism. Deiodinase type II activity was increased in hyperthyroid rat kidney only. Interestingly, in the heart, deiodinase type I-specific activity was increased fourfold, although the increase was not statistically significant. Cardiac deiodinase type I activity was detectable but not sensitive to thyroid status. Hepatic phenol-UGT as well as androsteron-UGT activities were decreased in hypothyroid rats, with specific androsteron-UGT activities two to three orders of magnitude lower than phenol-UGT activities. Both UGT isozymes were well above detection limits in heart, but appeared to be insensitive to thyroid status. In contrast, cardiac beta-glucuronidase activity decreased in hypothyroid tissue, whereas the activity of this enzyme in the other organs investigated did not change significantly.In summary, cardiac beta-glucuronidase, albeit in low levels, and hepatic phenol-UGT activities were responsive only to experimental hypothyroidism. Although a high basal activity of the pleiotropic beta-glucuronidase masking subtle activity changes in response to thyroid status cannot be ruled out, we conclude that hepatic, renal and cardiac UGT and beta-glucuronidase activities are not regulated reciprocally with thyroid status.

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L J W Jack, S Kahl, D L St Germain and A V Capuco

Abstract

Thyroxine 5′-deiodinase (5′D) catalyses deiodination of the prohormone thyroxine (T4) to the metabolically active hormone 3,5,3′-tri-iodothyronine (T3). Previously, it has been demonstrated that rat mammary gland expresses a 5′D with enzymatic properties equivalent to those of the type I enzyme (5′D-I) found in rat liver and kidney. Using complementary DNA (cDNA) for rat hepatic 5′D-I, we have examined expression of 5′D-I messenger RNA (mRNA) in liver, and mammary gland from virgin and lactating rats, and in seven other tissues from virgin rats. 5′D-I mRNA could not be detected in mammary gland either by Northern blotting or by the more sensitive technique of reverse transcribing mRNA and then amplifying the cDNA by polymerase chain reaction (RTPCR). Analysis of the seven tissues from virgin rats by RT-PCR showed 5′D-I amplicons in liver, kidney and thyroid. No amplicons were detected in adrenal gland, cardiac muscle, skeletal muscle or spleen. In addition, the effect of lactation intensity on circulating thyroid hormones, hepatic and mammary gland 5′D activity, and hepatic 5′D-I mRNA levels was examined. A strong inverse relationship was noted between increased lactation intensity (suckling burden) and circulating T4 and T3, hepatic 5′D-I activity and hepatic 5′D-I mRNA levels. Mammary gland 5′D activity was positively correlated to lactation intensity. The data presented strongly suggest that the 5′D activity expressed in lactating mammary gland is encoded by a mRNA different from the 5′D-I message found in rat liver, kidney and thyroid gland, and may help explain the differential regulation of 5′D-I activity in these organs during lactation. In addition, hepatic 5′D-I activity was found to be correlated with the concentration of 5′D-I mRNA, suggesting that regulation is pretranslational. Results are consistent with a previously suggested involvement of 5′D in establishing metabolic adaptations to support lactation.

Journal of Endocrinology (1994) 142, 205–215