Thyroxine mechanism

Some hydroxy metabolites of coplanar PCBs, such as 4-OH and 3,3 4,5 -tet-rachlorobiphenyl, act as antagonists of thyroxin (Chapter 6, Section 6.2.4). They have high affinity for the thyroxin-binding site on transthyretin (TTR) in plasma. Toxic effects include vitamin A deficiency. Biomarker assays for this toxic mechanism include percentage of thyroxin-binding sites to which rodenticide is bound, plasma levels of thyroxin, and plasma levels of vitamin A. 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

The amino acid tyrosine is the starting point in the synthesis of the catecholamines and of the thyroid hormones tetraiodothyronine (thyroxine T4) and triiodothyronine (T3) (Figure 42-2). T3 and T4 are unique in that they require the addition of iodine (as T) for bioactivity. Because dietary iodine is very scarce in many parts of the world, an intricate mechanism for accumulating and retaining T has evolved. 

The answer is c. (Hardman, pp 887, 889.) Bile acid-binding resins bind more than just bile acids, and binding of simvastatin to cholestyramine is the most likely mechanism for decreased Gl absorption. Cholestyramine may also bind to several other drugs, including digoxin, benzothiadiazides (thiazides), warfarin, vancomycin, thyroxine (T4), and aspirin. Medications should be given one hour before or four hours after cholestyramine. 

The concentration of Li+ in the thyroid is three to four times that in serum [179]. It is thought that Li+ may be concentrated in the thyroid gland by a mechanism similar to the incorporation of iodide, I-, resulting in competition between Li+ and I the levels of intracellular 1 decrease when those of Li+ increase, and vice versa [182]. Li+ inhibits both the ability of the gland to accumulate 1 and the release of iodine from the gland. In vitro, Li+ has no effect on thyroid peroxidase, the enzyme that catalyzes the incorporation of I" into tyrosyl residues leading to thyroidal hormone synthesis, but does increase the activity of iodotyrosine-deio-dinase, which catalyzes the reductive deiodination of iodotyrosyls, thus maintaining the levels of intracellular I [182]. The increase in iodoty-rosine-deiodinase activity is probably a response to the Li+-induced decrease in the concentration of thyroidal I". Li+ has no effect on the conversion of thyroxine to triiodothyronine. The overall effect of this competition between Li+ and 1 is, therefore, reduced levels of thyroid hormone in the presence of Li+. 

Thyroxine synthesis begins when iodide (I-) is transferred from the blood stream to the thyroid follicle cell by an active ATP-driven membrane pump mechanism this process is stimulated by cAMP following TSH stimulation of the gland. Iodide is transported through the follicular cell and secreted into the lumen of the follicle where it is oxidized to iodine and incorporated in to tyrosine residues by the enzyme thyroid peroxidase (TPO). 

Other hormones Thyroxine has long been known to increase metabolic rate, although the mechanism for this effect is not totally clear (Silvestri et al. 2005). More recently the hormone leptin, which is secreted by adipose tissue, has also been found to increase the metabolic rate. This effect of leptin is considered to play a role in controlling the amount of adipose tissue in the body, although this is a controversial subject (Chapter 12). 

Figure 12.8 Effector mechanism activation of a specific gene by hormone-receptor complex binding to DNA. A steroid is used to illustrate the mechanism. The hormone enters the cell and binds to its receptor (R) in the cytosol, the hormone-receptor complex enters the nucleus and binds to a specific sequence in the DNA that stimulates transcription of a gene or genes the resultant increase in mRNA increases the synthesis of specific proteins. The binding site on the DNA is specific and is usually termed a response element. Thyroxine (i.e. triiodothyronine) also uses this effector mechanism. Activation of genes, RNA processing to produce mRNA and translation are described in Chapter 20 (see Figures 20.20, 20.21 and 20.22).

The amino acids that are made available as a result of protein degradation in starvation are nsed as precursors of glucose, which is required for the brain. The decline in starvation-induced protein degradation is a result of the decreased requirement for glucose by the brain due to the increase in utilisation of ketone bodies. The qnestion arises, therefore, as to the mechanism by which the protein breakdown in muscle is reduced. Two answers, which are interdependent, have been put forward (i) decreased metabolic activity in tissues, and (ii) a decrease in the plasma level of thyroxine and hence triiodothyronine. 

Mechanism of Action Asynfheficisomer of thyroxine involved in normal metabolism, growth, and development, especially of fhe CNS in infants. Possesses catabolic and anabolic effects. Therapeutic Effect Increases basal metabolic rate, enhances gluco-neogenesis and stimulates protein synthesis. 

The coupling reaction by which the aromatic group from one residue of mono- or diiodotyrosine is joined in ether linkage with a second residue is also catalyzed readily by peroxidases. One dehydroalanine residue is formed for each molecule of hormone released.108 A possible mechanism involves formation of an electron-deficient radical, which can undergo (3 elimination to produce a dehydroalanine residue and an aromatic radical. The latter could couple with a second radical to form triiodothyronine or thyroxine. However, as depicted in Eq. 25-6, the radical coupling may occur prior to chain cleavage. While P elimination (pathway... 

Eukaryote organisms primarily respond to external signals by an initial signal perception by receptors. In general, such receptors can be either cytosolic or located on the plasma membrane [13-15]. The former mechanism applies to thyroid hormones (triiodothyronine and tetraiodothyronine or thyroxine), retinoids (e.g. retinoic acid), the insect developmental hormones such as ecdysone, steroid hormones (such as... 

There are relationships between the adrenal cortical hormones and the thyroid and pituitary glands. Depression or the function of the adrenals produces thyroid deficiency, w hereas administration of thyroxine stimulates the ACTH-adrenal conical mechanism. 

Propranolol inhibits the conversion of thyroxine (T4) to tri-iodothyronine (T3) by peripheral tissues (180), resulting in increased formation of inactive reverse T3. There have been several reports of hyperthyroxinemia in clinically euthyroid patients taking propranolol for non-thyroid reasons in high dosages (320-480 mg/day) (181,182). The incidence was considered to be higher than could be accounted for by the development of spontaneous hyperthyroidism, but the mechanism is unknown. 

Ma Y-A, Sih CJ, Flarms A (1999) Enzymatic Mechanism of Thyroxine Biosynthesis. Identification of the Lost Three-Carbon Fragment . J Am Chem Soc 121 8967... 

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