Thyroxine toxicity

The toxicity of thyroxine is directly related to the hormone level. In children, restlessness, insomnia, and accelerated bone maturation and growth may be signs of thyroxine toxicity. In adults, increased nervousness, heat intolerance, episodes of palpitation and tachycardia, or unexplained weight loss may be the presenting symptoms. If these symptoms are present, it is important to monitor serum TSH (Table 38-2), which will determine whether the symptoms are due to excess thyroxine blood levels. Chronic overtreatment with T4, particularly in elderly patients, can increase the risk of atrial fibrillation and accelerated osteoporosis. 

The term chiral recognition refers to a process m which some chiral receptor or reagent interacts selectively with one of the enantiomers of a chiral molecule Very high levels of chiral recognition are common m biological processes (—) Nicotine for exam pie IS much more toxic than (+) nicotine and (+) adrenaline is more active than (—) adrenaline m constricting blood vessels (—) Thyroxine an ammo acid of the thyroid gland that speeds up metabolism is one of the most widely used of all prescription... 

The toxicology of PCBs is complex and not fully understood. Coplanar PCBs interact with the Ah-receptor, with consequent induction of cytochrome P4501A1/2 and Ah-receptor-mediated toxicity. Induction of P4501A1 provides the basis of valuable biomarker assays, including bioassays such as CALUX. Certain PCBs, for example, 3,3, 4,4 -TCB, are converted to monohydroxymetabolites, which act as thyroxine antagonists. PCBs can also cause immunotoxicity (e.g., in seals). 

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. 

Rozman, K., T. Rozman, and H. Greim. 1984. Effect of thyroidectomy and thyroxine on 2,3,7,8-tetrachlorod-ibenzo-p-dioxin (TCDD) induced toxicity. Toxicol. Appl. Pharmacol. 72 372-376. 

Thyroid toxicity (decreased thyroxine levels and ultrastructural changes) was observed after rats were fed 2,000 mg/kg/day of di- -octylphthalate in the diet for 3, 10, or 21 days (Hinton et al. 1986). 

Administered in the drinking water of rats for 100 days, 1, 3, 10, or lOOmg/1 of iodine caused no signs of overt toxicity but some modifications of thyroid function occurred. Specifically, there was a dose-related trend in increased plasma thyroxine levels and a statistically significant increase in the thyroxine-to-triiodothyronine ratio. 

There is no final consensus on whether normal use of lithium, without any episode of toxicity (the vast majority of patients), may result in permanent renal impairment. Polyuria occurs in 20-40% and is due to inhibition of antidiuretic hormone (ADH) by lithium. It usually resolves on cessation of lithium as do any effects on glomerular function. Interference with thyroid function is due to inhibition of the action of thyroid stimulating hormone (TSH) and is easily managed by administration of thyroxine. Lithium is contraindicated during pregnancy (major vessel anomalies in fetus) and breastfeeding. 

Dronedarone is a structural analog of amiodarone and lacks iodine atoms. The design was intended to eliminate action of the parent drug on thyroxine metabolism and to modify the half-life of the drug. Dronedarone has multiple actions like amiodarone, blocking IKr, IKs, ICa, INa, and adrenoceptors. The drug has a half-life of 24 hours and was administered twice daily in the initial clinical trials. No thyroid or pulmonary toxicity has been noted during early use. 

Albumin is a major transport facilitator of hydrophobic compounds which would otherwise disrupt cellular membranes. These compounds include free fatty acids and bilirubin as well as hormones such as cortisol, aldosterone, and thyroxine when these materials have exceeded the capacity of proteins normally associated with them. Albumin also binds ions, including toxic heavy metals and metals such as copper and zinc which are essential for normal physiological functioning but may be toxic in quantities in excess of their binding capacity for their carrier proteins. Binding of protons is the basis for the buffering capacity of albumin. 

McKinney JD, Chae K, Oatley SJ, et al. 1985a. Molecular interactions of toxic chlorinated dibenzo-p-dioxins and dibenzofurans with thyroxine binding prealbumin. J Med Chem 28 375-381. 

McKinney JD, Fawkes J, Jordan S, et al. 1985b. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) as a potent and persistent thyroxine agonist A mechanistic model for toxicity based on molecular reactivity. Environ Health Perspect 61 41-53. 

Siegel NJ, Gaudio KM, Katz LA, et al. 1984. Beneficial effect of thyroxin on recovery from toxic acute renal failure. Kidney Int 25 906-911. 

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