Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Interference with thyroid serum binding protein transthyretin and subsequent adverse human neurodevelopmental toxicity||KE|
Level of Biological Organization
How this Key Event works
T4 (and T3) is actively transported across the cell membrane into target tissues through the action of specific carrier-mediated uptake (simple diffusion probably plays a minor role), where it is T3 that binds to and triggers the nuclear receptors in the target cells (Yen 2001, Zoeller et al 2007). The T3 supply is met via secretion from the thyroid (20%) and through conversion of T4 into T3 (80%) through the action of outer-ring deiodinase enzymes D1 and D3 (Chopra 1996 from Zoeller et al 2007). THs are cleared from serum by the liver following sulfation (via sulfotransferase enzymes) or glucuronidation (via UDP-glucuronosyl transferase enzymes) and ultimately, eliminated in the bile (Hood and Klaasen 2000).
Two major groups of transporters have been identified: organic anionic transport proteins (OATPs) and amino acid transporters (L- and T-type). Several of these transporters have displayed greater affinity and selectivity for T4 and T3 and specific compounds (such as polychlorinated biphenyls and polybrominated diethyl ethers) have been found to bind to the transport proteins either in serum or in various cellular compartments (Zoeller et al 2007)
OATPs transport both iodothyronines as well as sulfated conjugates and the gene family (SLCO) coding for this family of homologous proteins is clustered on human 12p12 (Hagenbuch and Meier 2004). OATP1A2 is expressed in brain, liver and kidney while OATP1B1, -1B2, and -1B3 are expressed in the liver and display high affinity for both T4 and T3 (Friesma et al 2005). OATP1C1 shows binding preference for T4 over T3 and is almost exclusively expressed in brain capillaries, where it is thought to play a role for transport of T4 across the blood brain barrier (Tohyama et al 2004).
There is also evidence that L-type or T-type amino acid transport proteins also play a role in cellular uptake of thyroid hormones. The former transport large neutral branched-chain and aromatic amino acids while the latter are specific to the aromatic amino acids Phe, Tyr and Trp (Visser 2010). The T-type amino acid transport protein TAT1 has been cloned from both rats and humans, is encoded by SLC16A10, and is a member of the monocarboxylate transporter (MCT) family (MCT10)(Kim et al 2002). Both MCT and MCT8 share a high degree of homology and are both highly effective iodothyronine transporters. MCT8 is highly selective for T4 and T, responsible for transporting T3 into neuronal cells and interferes with brain development if absent (Friesma et al 2003, 2006 and 2008). MCT8 is expressed in multiple tissues, including liver, kidney, heart, brain, placenta, thyroid, skeletal muscle and adrenal gland, while MCT10 is also expressed in various tissues, with high expression in muscle, intestine, kidney and pancreas and the former is known to only transport iodothyronine molecules while the latter can also carry aromatic amino acids (Nishimura et al 2008). In terms of transport efficacy, MCT10 appears to be superior to MCT8 for moving T3; however, the reverse is true for T4.
Uptake into hepatocytes is probably mediated through multiple low-affinity/high-capacity and high-affinity/low-capacity processes that can be inhibited by certain molecules, such as fatty acids, bilirubin and indoxyl sulfate (Henneman et al 2001). Km values for these processes are in the micro- to nanomolar range, while the serum concentrations of free T4 and T3 are in the picomolar range.
In order to reach the brain, T4 must cross either the blood-brain barrier (BBB) or the blood-cerebrospinal fluid (CSF) barrier. In serum, about 11% of T4 is transported via TTR; however, in CSF, up to 80% of thyroid hormones are bound to TTR and CSF probably contributes ~ 20% of the T4 found in the brain (Chanoine et al 1992). TTR is synthesized in the choroid plexus and secreted into the CSF and serum-bound TTR is not transported into CSF via choroid plexus in any significant amount (Chanoine et al 1992). In the brain, MCT8 is mostly expressed in neuronal cells of the hippocampus, cerebral cortex, striatum, hypothalamus and cerebellum but also in capillary endothelial cells and choroid plexus, as is OATP1C1 (Roberts et al 2008). It appears that MCT8 can transport T4 across both the BBB and the CSF barriers and that OATP1C1 can transport T4 across the CSF barrier. In addition, MCT8 is crucial for T3 transport into neurons and inactivation of this transporter can result in impaired development of the central nervous system (Visser 2010).
Pedraza et al (1993) and (1996) treated Wistar dams first with methimazole to block hormone synthesis followed by T4 and EMD 21388 (2.5 mg per day). Increased T3 (as generated from increased T4) was observed in both the maternal serum as well as placental component, as well as increased liver deiodinase activity.
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
Evidence Supporting Taxonomic Applicability
Chanoine, J.-P., Alex, S., Fang, S. L., Stone, S., Leonard, J. L., Kohrle, J., & Braverman, L. E. (1992). Role of transthyretin in the transport of thyroxine from the blood to the choroid plexus, the cerebrospinal fluid and the brain. Endocrinology, 130(2), 933–938.
Chopra 1996 from Zoeller et al 2007
Friesema EC, Jansen J, Jachtenberg JW, Visser WE, Kester MH, Visser TJ 2008 Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Molecular endocrinology (Baltimore, Md 22:1357-1369
Friesema EC, Kuiper GG, Jansen J, Visser TJ, Kester MH 2006 Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Molecular endocrinology (Baltimore, Md 20:2761-2772
Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ 2003 Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278:40128-40135
Hagenbuch B, Meier PJ 2004 Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 447:653-665
Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ 2001 Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocrine reviews 22:451-476
Hood and Klaasen 2000
Kim do K, Kanai Y, Matsuo H, Kim JY, Chairoungdua A, Kobayashi Y, Enomoto A, Cha SH, Goya T, Endou H 2002 The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. Genomics 79:95-103
Nishimura M, Naito S 2008 Tissue-specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab Pharmacokinet 23:22-44
Pedraza et al (1993)
Pedraza, P., Calvo, R., Obregón, M. J., Asuncion, M., Escobar Del Rey, F., & Morreale De Escobar, G. (1996). Displacement of T4 from transthyretin by the synthetic flavonoid EMD 21388 results in increased production of T3 from T4 in rat dams and fetuses. Endocrinology, 137(11), 4902–4914. http://doi.org/10.1210/en.137.11.4902
Roberts LM, Woodford K, Zhou M, Black DS, Haggerty JE, Tate EH, Grindstaff KK, Mengesha W, Raman C, Zerangue N 2008 Expression of the thyroid hormone transporters MCT8 (SLC16A2) and OATP14 (SLCO1C1) at the blood-brain barrier. Endocrinology 149:6251-6261
Tohyama K, Kusuhara H, Sugiyama Y 2004 Involvement of multispecific organic anion transporter, Oatp14 (Slc21a14), in the transport of thyroxine across the blood-brain barrier. Endocrinology
Visser, T. J. (2010). Cellular Uptake of Thyroid Hormones.
Yen, P. M. (2001). Physiological and molecular basis of thyroid hormone action. Physiological Reviews, 81(3), 1097–1142.
Zoeller, R. T., Tan, S. W., & Tyl, R. W. (2007). General background on the hypothalamic-pituitary-thyroid (HPT) axis. Critical Reviews in Toxicology, 37(1-2), 11–53.