Role of sulfation in thyroid hormone metabolism

doi:10.1016/0009-2797(94)90071-X

Chemico-Biological Interactions

Volume 92, Issues 1–3, June 1994, Pages 293-303

https://doi.org/10.1016/0009-2797(94)90071-X Get rights and content

Abstract

The type I iodothyronine deiodinase (ID-I) in liver and kidney converts the prohormone thyroxine (T₄) by outer ring deiodination (ORD) to bioactive 3,3′,5-triiodothyronine (T₃) or by inner ring deiodination (IRD) to inactive 3,3′,5-triiodothronine (rT₃), while it also catalyzes the IRD of T₃ and the ORD of rT₃, with the latter as the preferred substrate. Sulfation of the phenolic hydroxyl group blocks the ORD of T₄, while it strongly stimulates the IRD of both T₄ and T₃, indicating that sulfation is an important step in the irreversible inactivation of thyroid hormone. This review summarizes recent studies concerning this interaction between sulfation and deiodination of iodothyronines, the characterization of iodothyronine sulfotransferase activities, the measurement of iodothyronine sulfates in humans and animals, and the possible physiological importance of iodothyronine sulfation.

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Our results showed that AED suppressed dio2 gene expression and increased the T4 concentration, indicating the adverse effects of AED represent typical anti-thyroidal patterns. Sult1 st5 is very important for the homeostasis of T4 concentrations and can promote the elimination of T4 (Visser et al., 1994). Chronic exposure to PCP down-regulated the mRNA expression of the sult1 st5 gene in both male and female zebrafish (Yu et al., 2014).
Androstenedione (AED) is a naturally occurring androgen that is released into the environment through human and animal excretion. Several studies have shown that AED can interfere with the normal growth, development, and reproduction of organisms. However, studies examining the thyroid system, an important part of endocrine system of fish, are still lacking. This study examines thyroid hormone levels including T3 and T4, and transcriptional expression levels of genes associated with the hypothalamic-pituitary-thyroid axis (HPT axis) in adult zebrafish. Fish were exposed to a solvent control and three other concentrations of AED (0.2, 2.3, and 23.7 μg/L) for 60 days. Results indicated that AED significantly increased T4 levels but inhibited transcription of some HPT axis-related genes (nis, tpo, tg, dio1, dio2, sult1 st5, pax8, and nkx2.1) in female zebrafish. The adverse effects of AED on the thyroid system in males were very low, only affecting down-regulation of the tshb gene and up-regulation of the thrb gene. The overall results demonstrated that AED interferes with the thyroid endocrine system in fish.
The molecular basis of OH-PCB estrogen receptor activation
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Polychlorinated bisphenols (PCBs) continue to contaminate food chains globally where they concentrate in tissues and disrupt the endocrine systems of species throughout the ecosphere. Hydroxylated PCBs (OH-PCBs) are major PCB metabolites and high-affinity inhibitors of human estrogen sulfotransferase (SULT1E1), which sulfonates estrogens and thus prevents them from binding to and activating their receptors. OH-PCB inhibition of SULT1E1 is believed to contribute significantly to PCB-based endocrine disruption. Here, for the first time, the molecular basis of OH-PCB inhibition of SULT1E1 is revealed in a structure of SULT1E1 in complex with OH-PCB1 (4ʹ-OH-2,6-dichlorobiphenol) and its substrates, estradiol (E2), and PAP (3’-phosphoadenosine-5-phosphosulfate). OH-PCB1 prevents catalysis by intercalating between E2 and catalytic residues and establishes a new E2-binding site whose E2 affinity and positioning are greater than and competitive with those of the reactive-binding pocket. Such complexes have not been observed previously and offer a novel template for the design of high-affinity inhibitors. Mutating residues in direct contact with OH-PCB weaken its affinity without compromising the enzyme’s catalytic parameters. These OH-PCB resistant mutants were used in stable transfectant studies to demonstrate that OH-PCBs regulate estrogen receptors in cultured human cell lines by binding the OH-PCB binding pocket of SULT1E1.
Investigating the molecular mechanism of hydroxylated bromdiphenyl ethers to inhibit the thyroid hormone sulfotransferase SULT1A1
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Hydroxylated bromodiphenyl ethers (OH-BDEs) have raised great concern due to their potential endocrine disrupting effects on humans. In vitro experiments have indicated OH-BDEs can inhibit the activity of thyroid hormone (TH) sulfotransferases (SULTs); however, the molecular mechanism has not been investigated in depth. In this work, we employed 17 OH-BDEs with five or fewer Br atoms, and performed integrated computational simulations to unravel the possible inhibition mechanism of OH-BDEs on human SULT1A1. The molecular docking results demonstrate that OH-BDEs form hydrogen bonds with residues Lys106 and His108, and the neutral OH-BDEs show comparable binding energies with their anionic counterparts. The further hybrid quantum mechanical/molecular mechanical (QM/MM) calculations unravel a metabolic mechanism of OH-BDEs comprised by proton abstraction and sulfation steps. This mechanism is involved in the SULT1A1 inhibition by some OH-BDEs comprised of three or fewer Br atoms, while other OH-BDEs likely only form ternary complexes to competitively inhibit SULT1A1 activity. Moreover, the effect of the hydroxyl group of OH-BDEs on SULT1A1 inhibition potential follows the order of ortho-OH BDE > meta-OH BDE > para-OH BDE. These results provide an insight into the inhibition mechanism of OH-BDEs to SULT1A1 at the molecular level, which are beneficial in illuminating the molecular initiating events involved in the TH disruption of OH-BDEs.
The relationship between ingested thyroid hormones, thyroid homeostasis and iodine metabolism in humans and teleost fish
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Citation Excerpt :
Mammals have several sulfotransferases with an efficiency inversely related to the number of iodothyronine iodines (Sekura et al., 1981; Visser et al., 1990). Sulfate conjugates are preferred substrates for DIO1, resulting in negligible loss of sulfated TH in bile or urine (Bollman et al., 1965; Visser, 1994). Thus the iodine stripped from sulfate-TH conjugates is conserved.
Oral l-thyroxine (T4) therapy is used to treat human hypothyroidism but T4 fed to teleost fish does not raise plasma thyroid hormone (TH) levels nor induce growth, even though oral 3,5,3′-triiodo-l-thyronine (T3) is effective. This suggests a major difference in TH metabolism between teleosts and humans, often used as a starting thyroid model for lower vertebrates. To gain further insight on the proximate (mechanistic) and ultimate (survival value) factors underlying this difference, the several steps in TH homeostasis from intestinal TH uptake to hypothalamic-hypophyseal regulation were compared between humans and teleosts, and following dietary TH challenges. A major proximate factor limiting trout T4 uptake is a potent constitutive thiol-inhibited intestinal complete T4 deiodination that is ineffective for T3. At the hepatic level, T4 deiodination, conjugation and extensive biliary excretion with negligible T4 enterohepatic recycling can further block teleost T4 uptake to plasma. Such protection of plasma T4 from dietary T4 may be particularly critical for piscivorous fish consuming thyroid tissue, rich in T4 but not T3. It would prevent disruption by unregulated ingested T4 of the characteristic acute and transient changes in teleost plasma T4 due to diel rhythms, food intake and stress-related factors. These marked natural short-term fluctuations in teleost plasma T4 levels are enabled by the relatively small and rapidly-cleared plasma T4 pool, stemming largely from properties of the plasma T4-binding proteins. Humans, however, due mainly to plasma T4-binding globulin, have a relatively massive circulating pool of T4 and an extremely well-buffered free T4 level, consistent with the major TH role in regulating basal metabolic rate. Furthermore, this large well-buffered and slowly-cleared plasma T4 pool, in conjuction with enterohepatic recycling and relaxation of hypothalamic-hypophyseal negative feedback, allows humans to temporarily ‘store’ ingested T4 in plasma, thereby sparing endogenous TH secretion and conserving thyroidal iodine reserves. Indeed, iodine conservation is likely the key ultimate factor determining the divergent evolution of the human and teleost systems. For humans, ingested iodine in the form of I⁻, or TH and their derivatives, is the sole iodine source and may be limiting in many environments. However, most freshwater teleosts, in addition to their ability to assimilate dietary I⁻, can derive sufficient I⁻ from their copious gill irrigation, with no selective advantage in absorbing dietary T4 which would disrupt their natural acute and transient changes in plasma T4. Thus T4 may act also as a vitamin (vitamone) in humans but not in teleosts; in contrast, T3, naturally ingested at much lower levels, may act as a vitamone in both humans and teleosts.
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Role of sulfation in thyroid hormone metabolism

Abstract

Trends Endocrinol. Metab.

FEMS Microbiol. Rev.

Life Sci.

Intracellular pathways of iodothyronine metabolism

Importance of deiodination and conjugation in the hepatic metabolism of thyroid hormone

Biochemical characterization of triiodothyronine sulfotransferase

Sulfate transfer to thyroid hormones and their analogs by hepatic aryl sulfotransferase

Endocrinology

Triiodothyronine: a substrate for the thermostable and thermolabile forms of human phenol sulfotransferase

Endocrinology

Hepatic triiodothyronine sulfation and its regulation by growth hormone and triiodothyronine in rats

J. Biochem.

A study of triiodothyronine sulfation activity in rat tissues

Clin. Res.

The role of selenium in thyroid hormone action

Endocrinol. Rev.

Rapid and selective inner ring deiodination of thyroxine sulfate

Endocrinology

Rapid deiodination of triiodothyronine sulfate by rat liver microsomal fraction

Endocrinology

Deiodination of thyroid hormone by human liver

J. Clin. Endocrinol. Metab.

Kinetics of enzymic reductive deiodination of iodothyronines

Biochem. J.

Sulfation preceding deiodination of iodothyronines in rat hepatocytes

Science

Type I iodothyronine deiodinase is a selenocysteine-containing enzyme

Nature

Cloning and in vitro expression of the human selenoprotein, type I iodothyronine deiodinase

J. Clin. Endocrinol. Metab.

Deiodination of iodothyronine sulfamates by rat liver microsomes

Endocrinology

Metabolism of T3 by rat hepatocytes

Endocrinology

A study of metabolism of deaminated and sulfoconjugated iodothyronines by rat placental iodothyronine 5-monodeiodinase

Endocrinology

Metabolism of T₃ by rat hepatocytes