Studies on the biological activity of triiodothyronine sulfate.

Spaulding, Stephen W.; Smith, Terry J.; Hinkle, PM; Davis, Faith B.; Kung, Mei‐Ping; Roth, Jerome A.

doi:10.1210/jcem.74.5.1533227

Cited by 15 publications

(6 citation statements)

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“…However, T3S had no biological effect on the pituitary when tested in vitro (73,74), probably because it does not enter the pituitary cells (74). On the other hand, T3S was rapidly taken up and deiodinated in cultured hepatocytes (74).…”

Section: Effects On Tsh Secretionmentioning

confidence: 98%

Different Regulation of Thyroid Hormone Transport in Liver and Pituitary: Its Possible Role in the Maintenance of Low T3 Production during Nonthyroidal Illness and Fasting in Man

Everts¹,

Jong²,

Lim³

et al. 1996

Thyroid

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Nonthyroidal illness (NTI) and fasting in man are characterized by a low serum concentration of T3 and an increased serum concentration of rT3. Since the serum level of T3 is one of the most important factors that determine the metabolic rate, the low serum T3 during NTI or fasting results in reduction of the energy consumption of the body. This can be regarded as an adaptive mechanism to save energy, and thus to conserve protein and to protect organ function. The low serum T3 concentration should preferentially be maintained until recovery from illness or adequate calorie supply. This implies that the low serum T3 should not result in a rise in serum TSH. We postulate that different regulation of thyroid hormone transport into the relevant tissues, i.e., liver and pituitary, may play a role in maintenance of the low T3 production during NTI and fasting. This hypothesis is further elaborated in this paper by comparing (i) the properties of the thyroid hormone uptake mechanism in rat and human hepatocytes, perfused rat liver, and rat anterior pituitary cells, and (ii) the effects of fasting and conditions that mimic NTI on thyroid hormone transport in the same preparations. In addition, the consequences of changes in thyroid hormone transport and peripheral thyroid hormone metabolism during fasting and NTI for the serum level of rT3 and for TSH secretion are discussed. The data are compatible with the existence of different transport systems for thyroid hormone in liver and pituitary. We suggest that these different thyroid hormone carriers allow tissue-specific regulation of the intracellular availability of T3.

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Section: Effects On Tsh Secretionmentioning

confidence: 98%

Different Regulation of Thyroid Hormone Transport in Liver and Pituitary: Its Possible Role in the Maintenance of Low T3 Production during Nonthyroidal Illness and Fasting in Man

Everts¹,

Jong²,

Lim³

et al. 1996

Thyroid

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“…T 3 sulfate is detectable in the fetal circulation, and its concentration increases with fetal age (197). Although T 3 sulfate does not bind to nuclear receptors and therefore lacks intrinsic biological activity (198), sulfonation of iodothyronines is nevertheless an important metabolic step in determining their disposal (179). For instance, the majority of normal T 3 disposal occurs via T 3 sulfate formation (199).…”

Section: Sulfonation Of Thyroid Hormonesmentioning

confidence: 99%

Sulfonation and Molecular Action

2002

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The sulfonation of endogenous molecules is a pervasive biological phenomenon that is not always easily understood, and although it is increasingly recognized as a function of fundamental importance, there remain areas in which significant cognizance is still lacking or at most minimal. This is particularly true in the field of endocrinology, in which the sulfoconjugation of hormones is a widespread occurrence that is only partially, if at all, appreciated. In the realm of steroid/sterol sulfoconjugation, the discovery of a novel gene that utilizes an alternative exon 1 to encode for two sulfotransferase isoforms, one of which sulfonates cholesterol and the other pregnenolone, has been an important advance. This is significant because cholesterol sulfate plays a crucial role in physiological systems such as keratinocyte differentiation and development of the skin barrier, and pregnenolone sulfate is now acknowledged as an important neurosteroid. The sulfonation of thyroglobulin and thyroid hormones has been extensively investigated and, although this transformation is better understood, there remain areas of incomplete comprehension. The sulfonation of catecholamines is a prevalent modification that has been extensively studied but, unfortunately, remains poorly understood. The sulfonation of pituitary glycoprotein hormones, especially LH and TSH, does not affect binding to their cognate receptors; however, sulfonation does play an important role in their plasma clearance, which indirectly has a significant effect on biological activity. On the other hand, the sulfonation of distinct neuroendocrine peptides does have a profound influence on receptor binding and, thus, a direct effect on biological activity. The sulfonation of specific extracellular structures plays an essential role in the binding and signaling of a large family of extracellular growth factors. In summary, sulfonation is a ubiquitous posttranslational modification of hormones and extracellular components that can lead to dramatic structural changes in affected molecules, the biological significance of which is now beginning to be appreciated.

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“…Catecholamine mediated neurotransmission and neuronal cell death [9,48,49], thyroid hormone regulated energy metabolism [2–4], estrogen linked adipogenesis [50], HIV infection[51], olfaction [52] … are but a few of the scenarios in which SULT isoform-specific inhibition might be used to correct disease-linked metabolic imbalances. The specificity of each SULT isoform centers on a different area of metabolism; hence, as targets, SULTs provide the opportunity to regulate 13 different, disease-relevant metabolic networks.…”

Section: Resultsmentioning

confidence: 99%

“…Thyroid hormone (TH) regulates energy metabolism and development in humans [1]. TH is extensively sulfonated, which prevents TH-receptor binding and dramatically increases the efficiency with which TH is inactivated by Type 1 deiodinase [2–4]. Inhibition of SULT1A1 – the isoform that sulfonates TH – is expected to slow TH inactivation, and could thus prove of value in treating hypothyroidism.…”

Section: Introductionmentioning

confidence: 99%

Isoform-specific therapeutic control of sulfonation in humans

Cook

Wang

Leyh

2019

Biochemical Pharmacology

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The activities of hundreds, perhaps thousands, of metabolites are regulated by human cytosolic sulfotransferases (SULTs) – a 13-member family of disease relevant enzymes that catalyze transfer of the sulfuryl moiety (-SO3) from PAPS (3′-phosphoadenosine 5′-phosphosulfonate) to the hydroxyls and amines of acceptors. SULTs harbor two independent allosteric sites, one of which, the focus of this work, binds non-steroidal anti-inflammatory drugs (NSAIDs). The structure of the first NSAID-binding site – that of SULT1A1 – was elucidated recently and homology modeling suggest that variants of the site are present in all SULT isoforms. The objective of the current study was to assess whether the NSAID-binding site can be used to regulate sulfuryl transfer in humans in an isoform specific manner. Mefenamic acid (Mef) is a potent (Ki 27 nM) NSAID-inhibitor of SULT1A1 – the predominant SULT isoform in small intestine and liver. Acetaminophen (APAP), a SULT1A1 specific substrate, is extensively sulfonated in humans. Dehydroepiandrosterone (DHEA) is specific for SULT2A1, which we show here is insensitive to Mef inhibition. APAP and DHEA sulfonates are readily quantified in urine and thus the effects of Mef on APAP and DHEA sulfonation could be studied non-invasively. Compounds were given orally in a single therapeutic dose to a healthy, adult male human with a typical APAP-metabolite profile. Mef profoundly decreased APAP sulfonation during first pass metabolism and substantially decreased systemic APAP sulfonation without influencing DHEA sulfonation; thus, it appears the NSAID site can be used to control sulfonation in humans in a SULT-isoform specific manner.

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Studies on the biological activity of triiodothyronine sulfate.

Cited by 15 publications

References 0 publications

Different Regulation of Thyroid Hormone Transport in Liver and Pituitary: Its Possible Role in the Maintenance of Low T3 Production during Nonthyroidal Illness and Fasting in Man

Different Regulation of Thyroid Hormone Transport in Liver and Pituitary: Its Possible Role in the Maintenance of Low T3 Production during Nonthyroidal Illness and Fasting in Man

Sulfonation and Molecular Action

Isoform-specific therapeutic control of sulfonation in humans

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