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
Thyroxin (T4) and T3 are metabolized and cleared from tissues in a number of ways: inner ring or outer ring deiodination via specific enzymes, conjugation (glucuronidation or sulfation), oxidative deamination and ether-linked cleavage (Zoeller et al 2007).
There are three types of deiodinase enzymes. D1 and D2 convert T4 to T3 by removing an iodine atom from the outer ring while D3 removes an iodine atom from the inner ring, converting T4 to reverse T3. Differential expression of these enzymes during brain development are critical to the functionality of thyroid hormone in different areas of the fetal brain.
Much of the T4 is carried to the liver, where it is transported across the cellular membrane, converted into T3 via deiodination as mediated by deiodinase enzymes, and it is this T3 that triggers the TH receptors found in the nucleus. Roughly 80% of the T3 needed is produced via outer-ring deiodination of T4, which "activates" T4 to T3 (as opposed to inner-ring deiodination, which "degrades" T4 to reverse T3 which is eliminated). About 30% of the T4 produced daily (~ 130 nmol) is converted to roughly 40 nmol of T3 (Visser 2012) via enzyme D1 (liver, kidney) while conversion to rT3 accounts for roughly 40% of T4 turnover and is mediated via enzyme D3 (brain, placenta, fetus).
Glucuronidation and sulfation of T4 accounts for the rest of the metabolized T4 and leads to rapid elimination through bile. It is thought that 20% of daily T4 production is eliminated through biliary excretion of glucuronide conjugates. Glucuronidation is carried out by UDP-glucuronoyltransferase (UGT) enzymes (Hood and Klaassen 2000a, 2000b) and appears to be more important in murine species than in man (Henneman and Visser 1997) and sulfation of T4 is done largely through an initial inner ring deiodination step (via D3). Circulating levels of THs in serum can be affected by compounds that induce the activity of UDP-UGT enzymes.
Uptake into the liver involves "high affinity, low capacity" and "low affinity, high capacity" processes with Km values in the nano- to micro-molar range (as opposed to the free T3 and T4 concentrations, which are in the picomolar range) (Henneman et al 2001 from Visser 2010). Both MCT8 and MCT 10 can transport THs; however, MCT8 is expressed in human liver where MCT10 is not and MCT8 display higher efficacy of cellular uptake and efflux relative to T3 (Ref 12 in Visser 2010).
Martin et al (2012)
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?
Thyroid hormone uptake into human tissues has been measured by analyzing the rate of disappearance of radiolabeled TH from plasma into rapidly and slowly equilibrating tissue compartments (Visser 2010).
Measuring the rate of T4 glucuronidation and sulfation as well as biliary excretion informs the mechanism of action of thyroid system modulation. Studies involving knock/out mice and thyroidectomized rats also inform this mechanism.
Evidence Supporting Taxonomic Applicability
Henneman et al 2001 from Visser 2010
Henneman and Visser 1997
Hood and Klaassen 2000a, 2000b
Visser, T. J. (2010). Cellular Uptake of Thyroid Hormones.
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.