Differences between the effects of thyroxine and tetraiodothyroacetic acid on TSH suppression and cardiac hypertrophy

Abstract

Objective: We earlier reported marked qualitative differences between the effect of 3,5,3H -triiodothyroacetic acid (Triac) and tri-iodothyronine (T 3 ) on cardiac hypertrophy at equivalent thyroidstimulating hormone (TSH)-suppressive doses. We have now extended these studies to specific cardiac parameters. Due to its rapid metabolic clearance rate, Triac is not suitable for TSH suppression and therefore the slowly metabolized 3,5,3H ,5 H -tetraiodothyroacetic acid (Tetrac), the precursor of Triac, was studied. Methods: Hypothyroid rats were infused over 13 days with 1.5±40.5 nmol Tetrac/day per 100 g body weight (BW) or with 0.5±13.5 nmol thyroxine (T 4 )/day per 100 g BW. Results: The responses of serum TSH and of hepatic monodeiodinase type 1 were parallel for both hormones, their potency ratios could therefore be compared. Tetrac was revealed as being only half as active on hepatic monoiodinase type 1 despite a similar serum TSH levels. Tetrac can therefore be considered to have a preferential action on serum TSH suppression. The cardiac effects on Ca 2+ -ATPase (SERCA 2a) and monodeiodinase type 1 activity were qualitatively different and therefore one cannot give an overall quantitative estimate of these differences. The results showed clearly, however, that Tetrac is less efficient for all parameters studied, namely induction of cardiac hypertrophy, amyosin heavy chain mRNA, monodeiodinase type 1 activity and mRNA levels of the sarcoplasmic SERCA 2a. Conclusion:We postulate therefore that, in the rat and possibly in man, Tetrac could represent a favorable alternative for suppression of serum TSH levels.

Uptake of triiodothyronine and triiodothyroacetic acid in neonatal rat cardiomyocytes: effects of metabolites and analogs

“…Tetrac has also been reported to be more effective than T 4 in suppressing TSH secretion in vivo in hypothyroid rats (Lameloise et al 2001), whereas it was less effective in inducing cardiac hypertrophy. In our study, the inhibitory effect of T 4 (around 25%) on T 3 uptake was, if anything, greater than that of Tetrac, albeit not significantly so.…”

“…In addition, tetraiodothyroacetic acid (Tetrac) was more potent than T 4 in reducing TSH release in isolated pituitary cells (Everts et al 1995) and in hypothyroid rats (Lameloise et al 2001), but it was less efficient in inducing cardiac hypertrophy (Lameloise et al 2001). Recent work on mitochondria indicates that T 3 metabolites such as 3,5-diiodothyronine (3,5-T 2 ) may have thermogenic effects (Goglia et al 1999).…”

Translational implications of nongenomic actions of thyroid hormone initiated at its integrin receptor

“…Nanoparticulate tetrac cannot gain access to the cell interior and is exclusively a thyroid hormone antagonist at the integrin. This feature of exclusion is desirable, since unmodified tetrac within the cell has low-grade, but appreciable, thyromimetic activity (30).…”

“…Tetrac is an analog of T4 that inhibits binding of T4 and T3 to the TR on integrin ␣v␤3 and thus blocks the actions of agonist thyroid hormone analogs on cancer cell proliferation and on angiogenesis. 4) Covalently bonded to a nanoparticle (NP), tetrac NP acts exclusively at the cell surface thyroid hormone integrin receptor and by not entering the cell is unable to express low-grade, nucleusmediated thyromimetic activity that the unmodified molecule possesses (30). Acting at the cell surface receptor and in the absence of T4 and T3, tetrac may also affect gene expression in cancer cells (16).…”

In vitro pituitary and thyroid cell proliferation assays and their relevance as alternatives to animal testing

“…Effect of increasing serum levels of A) T4 and tetrac (data from Lameloise et al, 2001) and B) T3 and triac (data from Liang et al, 1997) on relative heart weight (expressed as % of total body weight). jective was to develop an in vitro thyroid cell proliferation assay and explore correlations between the in vitro data obtained and in vivo data for compounds known to affect thyroid weight (OeCD, 2007).…”