Transthyretin thyroxine-binding

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. 

Brouwer, A., E. Klasson-Wehler, M. Bokdam, D.C. Morse, and W.A. Traag. 1990. Competitive inhibition of thyroxin binding to transthyretin by monohydroxy metabolites of 3,3, 4,4 -tetrachlorobiphenyl. Chemo-sphere 20 1257-1262. 

Thyroxine-binding globulin is the least abundant of the three major transport proteins. Nevertheless, it carries about 70% of the circulating T4 and Tj by virtue of its high affinity for the two hormones. Transthyretin, formerly known as thyroxine-binding prealbumin, binds only about 10 to 15% of the hormones. Albumin, a protein that has a binding affinity for a multitude of small molecules, has an even lower affinity for T4 and T3 than... 

Lans MC, Spiertz C, Brouwer A, et al. 1994. Different competition of thyroxine binding to transthyretin and thyroxine-binding globulin by hydroxy-PCBs, PCDDs and PCDFs. Eur J Pharmacol 270 129-136. 

A. Wojtczak et al., Structure of rat transthyretin (rTTR) complex with thyroxine at 2.5 A resolution First non-biased insight into thyroxine binding reveals different hormone orientation in two binding sites. Acta. Cryst. D 57, 1061-1070 (2001)... 

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). 

LBM includes skeletal muscle, somatic protein, and functional proteins such as circulating proteins and the visceral proteins. Biochemically, LBM can be assessed by measuring the serum visceral proteins, albumin (ALB), transferrin (TFN), and prealbumin (thyroxine-binding prealbumin or transthyretin). Other serum proteins, such as retinol-binding protein, flbronectin (an opsonic protein), and somatomedin-C (insulin-like growth factor-1), that have a very short half-life (less than 12 to 24 hours), have been suggested as... 

In plasma, over 99.95% of T4 is transported bound to proteins. Thyroxine binding globulin (TBG) carries 70% of Tj, albumin approximately 25% and transthyretin (formerly called prealbumin) around 5%. Over 99.5% of T, is transported by the same proteins. It is the unbound, or free . Tj and Tj concentrations which arc important for the biological effects of the hormones, including the feedback to the pituitary and hypothalamus. Changes in binding protein concentration complicate the interpretation of thyroid homione results, e.g. in pregnancy. 

T3, T4, and 1T3 are released from the basement membrane of the follicle and enter the blood, where they are bound to carrier proteins synthesized by the liver. These proteins are alpha-globulins called thyroxine binding globulins (TBGs), transthyretin... 

Pettersson TM, Carlstrom A, Ehrenberg A, Jomvall H (1989) Transthyretin microheterogeneity and thyroxine binding are influenced by non-amino acid components and glutathione constituents. Biochem Biophys Res Commun 158 341-347... 

Zheng, W., Lu, Y.M., Lu, G.Y., Zhao, Q., Cheung, O., Blaner, W.S., 2001. Transthyretin, thyroxine, and retinol-binding protein in human spinal fluid effect of lead exposure. Toxicol. Sci. 61, 107-114. 

Vitamin A is transported m the plasma as retinol bound to a carrier protein, called retinol-binding protein (RBP), which itself forms a complex with the thyroxine-binding protein, known as transthyretin (TTR). This complex exists in equilibrium with free holo-RBP, which can then interact with a specific cell-surface receptor, thereby inducing the release of its retinol to the target cell. Thus, RBP possesses at least three molecular-recognition properties it binds retinol and it interacts with both TTR and the cell-surface receptor (for reviews, see refs. I and 2). 

Smith TJ, Davis FB, Deziel MR, Davis PJ, Ramsden DB, Schoenl M (1994) Retinoic acid inhibition of thyroxine binding to human transthyretin. Biochim Biophys Acta 1199 76-89... 

When stimulated to release thyroid hormones, thyroglobulin is degraded through the activity of lysosomes and T3 and T4 are released and rapidly enter the circulation. Iodide freed in this reaction is for the most part recycled and the iodinated tyrosine reused for hormone production. Nearly all of the released hormones are rapidly bound to transport hormones, with 70% bound to thyroxine binding globulin (TBG). Other proteins, such as transthyretin (TTR), albumin, and lipoproteins, bind most of the remainder with significant differences in the strengths of the affinity for the hormones, these proteins transport the hormones to different sites. 

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