Thyroid hormone transport, transthyretin

Tetrabromobisphenol A (4,4 -isopropylidenebis(2,6-dibromophenol) TBBPA) is the most widely used BFR in terms of production quantities [2]. It is used as both a reactive and an additive BFR in a variety of polymers, epoxy resins, and adhesives and, in particular, is a constituent in printed circuit boards at levels up to 34% (mass fraction). The acute toxicity of TBBPA is relatively low however, concern for its potential as an endocrine disrupter exists. TBBPA shares structural similarities to thyroxine (T4), and the compoimd competitively binds to the thyroid hormone transport protein transthyretin [135]. Analysis by gas chromatography requires derivitization, and LC methods are preferred to reduce sample processing. Biotransformation of TBBPA... 

The failure of proteins to fold into their functional forms can occasionally lead to "misfolding" or "conformational" diseases.140 Many of these diseases are associated with the formation of amyloid protein, an insoluble material that is deposited as fibrils or plaques in different tissues and organs of the body. They include amyloid Ap protein as the major constituent of the plaques in Alzheimer patients, PrPc associated with neuro-degenerative diseases, a-synuclein (AS) associated with Parkinson s diseases, transthyretin (TTR) as a homotetrameric protein that is involved in the transport of thyroid hormones and retinol in human serum. In particular, the Ap protein is a peptide of 39-43 amino acids that is the... 

Transport. A wellknown transport protein is hemoglobin in the erythrocytes (bottom left). It is responsible for the transport of oxygen and carbon dioxide between the lungs and tissues (see p.282). The blood plasma also contains many other proteins with transport functions. Prealbumin (transthyretin middle), for example, transports the thyroid hormones thyroxin and triiodothyronine. Ion channels and other integral membrane proteins (see p.220) facilitate the transport of ions and metabolites across biological membranes. 

When vitamin A stores are adequate, the liver secretes retinol bound to retinol-binding protein (RBP) into the circulation to provide tissues with a constant supply of vitamin A. In the circulation, the retinol-RBP complex is found bound to another circulating protein of hepatic origin, transthyretin (TTR). TTR also binds thyroid hormone and consequently plays a role in the transport of both vitamin A and thyroid hormone. The molecular size of the retinol-RBP complex is quite small, and the formation of the... 

Transthyretin (prealbumin) and retinol-binding protein (RBP) are transport proteins that migrate together as a 1 1 molecular complex. Transthyretin was originally named prealbumin because of its electrophoretic mobility it was renamed in 1981 to reflect its binding and transport of both thyroid hormones (thyroxine and triiodothyronine) and RBP. 

PCBs, including poly-ort/jo-substituted PCBs, which have a very low affinity for the Ah receptor, inhibit the binding of T4 to transthyretin, an important transport protein for both T4 and T3 (Chauhan et al. 2000 Cheek et al. 1999 Darnerud et al. 1996a). Inhibition of binding of thyroid hormones to transthryetin could alter hormone delivery to target tissues, including the brain, and could also result in depressed levels of serum total TT4 or TT3 (Brouwer et al. 1998). 

For example, alternative transcription-control elements regulate expression of the mammalian gene that encodes transthyretin (TTR), which transports thyroid hormone in blood and the cerebrospinal fluid that surrounds the brain... 

RBP interacts strongly with another protein, plasma transthyretin (TTR, also more commonly referred to as plasma prealbumin) and normally circulates as a 1 1 molar RBP-TTR complex. [The name transthyretin has been suggested (Nomenclature Committee of lUB et al., 1981) for the protein usually called prealbumin and will be used instead of the term prealbumin in this and other chapters.] The usual level of RBP in plasma is about 40-50 p,g/ml and that of TTR is about 200-300 pg/ml. In addition to its role in vitamin A transport, TTR plays a role in the binding and plasma transport of thyroid hormones. The formation of the RBP-TTR complex serves to reduce the glomerular filtration and renal catabolism of RBP. 

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. 

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. 

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