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Event Title

Free serum thyroxine (T4), Increased

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

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

Following displacement of T4 from its binding site on TTR by some competitive ligand (like EMD 21388, etc.), the T4 joins the small pool of free hormone found in serum. This increases the amount of free T4 and has been demonstrated in animal models following administration of a xenobiotic competitive ligand.

Kohrle et al (1989) administered 2 umol of EMD 21388 per 100g BW in a single ip injection to euthyroid adult male Sprague-Dawley rats. Rat serum was analyzed for T3 and T4 content via species-adapted RIA and percent free TH was determined via equilibrium dialysis. Serum T4 decreased significantly following 1 hr or administration and remained low for several hours, while % free T4 increased significantly at 1 hr and remained elevated. {insert Figure 5} Previously, both in vitro and in vivo electrophoretic data showed complete inhibition of radiolabeled T4 binding to TTR. Administration of EMD 21388 to rats did not impact T3 concentrations or deiodinase activity.

Lueprasitsakul et al (1990) also administered EMD 21388 to euthyroid adult male Sprague-Dawley rats as a single 2 umol ip injection with additional time points as well as a single injection of 0.3 umol. In addition, one treatment group were exposed to varying doses from 0.2 to 2 umol EDM21388 per 100 g BW. Significant decreases in radiolabeled T4 bound to TTR were found within 3 minutes, reaching a maximum at 10 minutes. A simultaneous increase in % free T4 was noted at 3 minutes and reached a maximum at 10 minutes. {insert Figure 3} These effects were observed for both the high dose of 2 umol and the low dose of 0.3 umol; however, it was noted that % T4 bound to TTR recovered to almost control levels after 3 hours at the low dose. The authors concluded that EMD 21388 administration increased both the free T4 concentration as well as the albumin-bound T4 (which is available in serum and can play a greater role in transport when needed).

Mendel et al (1992) performed additional kinetic studies with radiolabeled T4 and albumin using Sprague-Dawley rats receiving a single ip injection of 2 umol EMD 21388. To overcome the dilution effect found with equilibrium dialysis, ultrafiltration of undiluted serum was employed to measure the % free T4. The % free T4 increased significantly at 20 minutes and the compensatory response of albumin appears to have been saturated after 20 minutes, as shown by the plasma disappearance curve for radiolabeled albumin. {insert Figures 2 and 3} The authors concluded that these data did not confirm TTR is a major carrier of T4 from plasma to liver and other tissues; however, these data also did not distinguish between whether transfer in vivo could be via albumin or from the free pool of T4 in serum.

Chanoine et al (1992) administered low (0.3 umol) and high dose (2 umol) EMD 21388 to Sprague-Dawley rats via single ip injection and a second treatment group had radiolabeled T4 injected 15 minutes following the EMD 21388 adminisatration. Both doses produced a similar significant increase to free T4 in serum within 15 minuteas of administration. {insert Figure 1} Binding of T4 to albumin in serum increased an order of magnitude in both high and low dose treatments. The low dose had no effect on the %T4 bound to TTR in the choroid plexus or the cerebrospinal fluid; however, the high dose did significantly decrease this. {insert Figure 2}

Pedraza et al (1996)

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?

Total T4 is most often measured using a serum-based diagnostic kit; however, free T4 is considered a more reliable measure of thyroid dysfunction and the only direct measurements for unbound thyroid hormone are equilibrium dialysis and ultrafiltration (Zoeller et al 2007). Large volumes of serum must be used to capture the very low concentrations of free THs and this requires pooling in non-adult animals.

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.

Kohrle, J., S.L. Fang, Y. Yang, K. Irmscher, R.D. Hesch, S. Pino, S. Alex, and L.E. Braverman. (1989). Rapid effects of the flavonoid EMD 21388 on serum thyroid hormone binding and thyrotropin regulation in the rat. Endocrinology 125: 532-537

Lueprasitsakul, W., Alex, S., Fang, S. L., Pino, S., Irmscher, K., Köhrle, J., & Braverman, L. E. (1990). Flavonoid administration immediately displaces thyroxine (T4) from serum transthyretin, increases serum free T4, and decreases serum thyrotropin in the rat. Endocrinology. 126: 2890-2895

Mendel, C. M., Cavalieri, R. R., & Kohrle, J. (1992). Thyroxine (T4) transport and distribution in rats treated with EMD 21388, a synthetic flavonoid that displaces T4 from transthyretin. Endocrinology, 130(3), 1525–1532.

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