Vitamin Thyroxine

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. 

Transthyretin (TTR) A protein complex found in blood that binds both retinol (vitamin A) and thyroxine. 

Tests to exclude possible causes of dementia include a depression screen, vitamin B12 deficiency, thyroid function tests [thyroid-stimulating hormone (TSH) and free triiodothyronine and thyroxine], complete blood cell count, and chemistry panel.21... 

Other potential adverse effects include impaired absorption of fat-soluble vitamins A, D, E, and K hypernatremia and hyperchloremia GI obstruction and reduced bioavailability of acidic drugs such as warfarin, nicotinic acid, thyroxine, acetaminophen, hydrocortisone, hydrochlorothiazide, loperamide, and possibly iron. Drug interactions may be avoided by alternating administration times with an interval of 6 hours or greater between the BAR and other drugs. 

Calcium is the major mineral component of bone and normal repair and remodelling of bone is reliant on an adequate supply of this mineral. Calcium uptake in the gut, loss through the kidneys and turnover within the body are controlled by hormones, notably PTH and 1,25 dihydroxy cholecalciferol (1,25 DHCC or 1,25 dihydroxy vitamin D3 or calcitriol). Refer to Figure 8.12 for a summary of the involvement of PTH and vitamin D3 in controlling plasma calcium concentration. These two major hormones have complementary actions to raise plasma calcium concentration by promoting uptake in the gut, reabsorption in the nephron and bone resorption. Other hormones such as thyroxine, sex steroids and glucocorticoids (e.g. cortisol) influence the distribution of calcium. 

Iodine is essential in the mammalian diet to produce the thyroid hormone thyroxine deficiency in humans causes goitre. Collectively, deficiencies of iodine, iron, zinc and vitamin A in humans are thought to be at least as widespread and debilitating as calorie deficiencies (Welch and Graham, 1999). The main source of iodine in soils is oceanic salts rather than parent rock, and so deficiency is most widespread in areas remote from the sea (Fuge, 1996). In principle deficiency is easily corrected with dairy supplements. However in practice this is not always feasible. Addition of iodate to irrigation water has successfully corrected widespread iodine deficiency in parts of China where the usual methods of supplementation had failed (Cao et al., 1994 Jiang et al 1997). However there is not much information on the behaviour of iodine in soil and water systems. 

During the acute phase of thyrotoxicosis, B-adrenoceptor blocking agents without intrinsic sympathomimetic activity are extremely helpful. Propranolol, 20-40 mg orally every 6 hours, will control tachycardia, hypertension, and atrial fibrillation. Propranolol is gradually withdrawn as serum thyroxine levels return to normal. Diltiazem, 90-120 mg three or four times daily, can be used to control tachycardia in patients in whom blockers are contraindicated, eg, those with asthma. Other calcium channel blockers may not be as effective as diltiazem. Adequate nutrition and vitamin supplements are essential. Barbiturates accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4... 

Some humans unable to respond to cortisol, testosterone, vitamin D, or thyroxine have mutations of this type. 

Antagonists of riboflavin include isoriboflavin, lumiflavin, aiaboflavin, hydroxyethyl analogue, formyl methyl analogue, galactoflavin, and flavin-monosulfate. Synergists include vitamins A. B, B(l, and B12, niacin, pantothenic acid, folic acid, biotin, tetraiodothyronine (thyroxine), insulin, and somatotrophin (growth hormone). 

Possible consequences of the loss of binding proteins (e.g., ceruloplasmin, transferrin, vitamin D-binding protein, thyroxin-binding globulin, and cortisol-binding protein) have been already mentioned. 

Hormones Some lipophilic hormones (e.g. the steroid hormones, thyroxine, retinoic acid and vitamin D) diffuse across the plasma membrane and interact with intracellular receptors in the cytosol or nucleus. Other lipophilic hormones (e.g. the prostaglandins) and hydrophilic hormones (e.g. the peptide hormones insulin and glucagon and the biogenic amines epinephrine and histamine) bind to receptor proteins in the plasma membrane. 

Small lipophilic (lipid-soluble) hormones diffuse across the plasma membrane and then interact with intracellular receptors in the cytosol or nucleus. The resulting hormone-receptor complex often binds to regions of the DNA and affects the transcription of certain genes (see Topic G7). Small lipophilic hormones with intracellular receptors include the steroid hormones which are synthesized from cholesterol (see Topic K5) (e.g. the female sex hormones estrogen and progesterone), thyroxine which is produced by thyroid cells and is the principal iodinated compound in animals, retinoic acid which is derived from vitamin A, and vitamin D which is synthesized in the skin in response to sunlight (see Topic K5). 

An absence of R-type binding protein has been reported in two adult siblings by Carmel and Herbert (C20). R-Type protein was virtually absent from their leukocytes and saliva, and as was expected they had very low levels of serum vitamin B12. The absence of the protein did not appear to have any adverse effects. Other members of this family have also been found to have an absence of, or very low levels of, R-protein (H26). There was no general deficiency of plasma glycoproteins in these patients and the amounts of thyroid binding globulin, thyroxine, ceruloplasmin, and transferrin were all normal. 

Fig. 2. Basic structure of receptors for progesterone (PR), glucocorticoid (GR), oestradiol (ER), thyroxine (T3) and vitamin D (Vit D). The receptors are divided into six domains, A-F [15] and the per-entage homology of region C for each receptor is compared with that for the progesterone receptor [9-14]. The number of amino acids in each receptor is shown on the right-hand side.

RBP forms a 1 1 complex with the tetrameric thyroxine-binding prealbumin, transthyretin. This is important to prevent urinary loss of retinol bound to the relatively small RBP (Mr 21,000), which would be filtered by the glomerulus transthyretin has an Mr of 54,000 hence, the complex will not normally be filtered, ffowever, moderate renal damage, or the increased permeability of the glomerulus in infection, may result in considerable loss of vitamin A bound to RBP-transthyretin. 

Metabolites of polychlorinated biphenyls bind to the thyroxine binding site of transthyretin and, in doing so, impair the binding of RBP. As a result of this, there is free RBP-bound retinol in plasma, which is filtered at the glomerulus andhence lost in the urine. This may account for the vitamin A depleting action of polychlorinated biphenyls (Brouwer and van den Berg, 1986). 

Brouwer A and van den Berg KJ (1986) Binding of a metabolite of 3,4,3, 4 -tetra-chlorobiphenyl to transthyretin reduces serum vitamin A transport by inhibiting the formation of the protein complex carrying both retinol and thyroxin. Toxicology and Applied Pharmacology 85,301-12. 

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