RESUMO
Until recently, 3,5-diiodothyronine (3,5-T(2)) has been considered an inactive by-product of triiodothyronine (T(3)) deiodination. However, studies from several laboratories have shown that 3,5-T(2) has specific, nongenomic effects on mitochondrial oxidative capacity and respiration rate that are distinct from those due to T(3). Nevertheless, little is known about the putative genomic effects of 3,5-T(2). We have previously shown that hyperthyroidism induced by supraphysiological doses of 3,5-T(2) inhibits hepatic iodothyronine deiodinase type 2 (D2) activity and lowers mRNA levels in the killifish in the same manner as T(3) and T(4), suggesting a pretranslational effect of 3,5-T(2) (Garcia-G C, Jeziorski MC, Valverde-R C, Orozco A. Gen Comp Endocrinol 135: 201-209, 2004). The question remains as to whether 3,5-T(2) would have effects under conditions similar to those that are physiological for T(3). To this end, intact killifish were rendered hypothyroid by administering methimazole. Groups of hypothyroid animals simultaneously received 30 nM of either T(3), reverse T(3), or 3,5-T(2). Under these conditions, we expected that, if it were bioactive, 3,5-T(2) would mimic T(3) and thus reverse the compensatory upregulation of D2 and tyroid receptor beta1 and downregulation of growth hormone that characterize hypothyroidism. Our results demonstrate that 3,5-T(2) is indeed bioactive, reversing both hepatic D2 and growth hormone responses during a hypothyroidal state. Furthermore, we observed that 3,5-T(2) and T(3) recruit two distinct populations of transcription factors to typical palindromic and DR4 thyroid hormone response elements. Taken together, these results add further evidence to support the notion that 3,5-T(2) is a bioactive iodothyronine.
Assuntos
Di-Iodotironinas/farmacologia , Fundulidae/fisiologia , Hormônio do Crescimento/sangue , Iodeto Peroxidase/metabolismo , Glândula Tireoide/fisiologia , Receptores beta dos Hormônios Tireóideos/metabolismo , Animais , Di-Iodotironinas/sangue , Regulação Enzimológica da Expressão Gênica/fisiologia , Hipertireoidismo/metabolismo , Hipertireoidismo/fisiopatologia , Hipotireoidismo/metabolismo , Hipotireoidismo/fisiopatologia , Iodeto Peroxidase/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , RNA Mensageiro/metabolismo , Elementos de Resposta/fisiologia , Glândula Tireoide/efeitos dos fármacos , Regulação para Cima/fisiologia , Iodotironina Desiodinase Tipo IIRESUMO
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.
Assuntos
Hidrolases/metabolismo , Iodeto Peroxidase/metabolismo , Glândula Tireoide/enzimologia , Animais , Ativação Enzimática , Feminino , Hidrolases/análise , Iodeto Peroxidase/análise , Radioisótopos do Iodo/metabolismo , Masculino , NADP/metabolismo , Oxirredução , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
The kinetic characterization of the outer-ring deiodination pathway using rT(3) (rT(3)-ORD) in male, female, and pregnant female livers of an endemic lizard, Sceloporus grammicus, is reported. The ORD pathway does not have the characteristics of deiodinase type II; it is exclusively carried out by deiodinase type I (DI). DI enzymatic activity in lizard liver contains one of the highest activities reported in vertebrates. This activity is sexually dimorphic, with males presenting the highest activity during the reproductive season. The properties of this enzyme correspond to those described in mammals, such as specificity for rT(3), susceptibility to inhibition by 6-n-propyl-2-thiouracil and gold-thioglucose, cofactor requirement, and kinetic pattern. Unlike other vertebrates, the lizard DI exhibits conspicuous stability in the thermal range of 15 to 42 degrees C and in the pH range of 5.0 to 9.0. Male true kinetic constants exhibit a direct correlation with temperature. This is in agreement with short-term adaptation to microenvironmental changes and the feasible expression of enzymatic forms/variants which, together, endow this lizard species with a greater adaptation to natural daily ambient thermal fluctuations.
Assuntos
Iodeto Peroxidase/metabolismo , Fígado/enzimologia , Lagartos/metabolismo , Animais , Aurotioglucose/farmacologia , Ditiotreitol/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Concentração de Íons de Hidrogênio , Iodeto Peroxidase/antagonistas & inibidores , Cinética , Masculino , Gravidez , Propiltiouracila/farmacologia , Estações do Ano , Caracteres Sexuais , Temperatura , Tri-Iodotironina Reversa/metabolismoAssuntos
Adenoma/ultraestrutura , Neoplasias Hipofisárias/ultraestrutura , Prolactina/metabolismo , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adulto , Bromocriptina/uso terapêutico , Feminino , Humanos , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/metabolismoRESUMO
As a result of a great deal of experimental and clinical research during the past 20 years, it is now clear that the final common pathway between central nervous system and anterior pituitary function is bridged by a new family of neurohormones, the so called hypothalamic hormones. These products released into the hypothalamo-hypophyseal portal system act directly on the adenohypophysis to increase or decrease the release of each of the known pituitary tropic hormones. The molecular structures of several of these hypothalamic hormones have been established and their synthesis achieved. Recent physiological studies have shown that they constitute an ideal tool with important clinical and veterinary applications.