Thyroid hormone conjugation

OatplaS was cloned fromratretinaandintestine [41,44]. Consequently, theexpression of OatplaS protein could not be demonstrated unequivocally in liver or kidney. In addition, OatplaS rather than Oatplal is expressed at the apical plasma membrane of rat choroid plexus epithelial cells [45]. As Oatplal is not expressed in the intestine, expression of OatplaS could clearly be shown at the apical membranes of small intestinal epithelial cells [44]. The 670-amino acid protein shares 80% amino acid identity with Oatplal. OatplaS can transport bile salts, steroid hormone conjugates, thyroid hormones, cardiac glycosides, and oligopeptides (Table 3.2) [26, 46, 47]. 

The functional form of thyroxine (T3) is generated by the deiodination of T4, and PCBs can influence the tissue levels of this form by disturbing metabolism, as well as by reducing the binding of T4. PCBs have been shown to inhibit the sulfation of thyroid hormones and the deiodination of T4 to T3. They can also induce the glucuronyl transferase that conjugates T4 (Brouwer et al. 1998). 

PNP-DTP has been used to photoaffinity label the thyroid hormone nuclear receptors in intact cells by preparing a derivative of 3,5,3 -triiodo-L-thyronine with the crosslinker (Pascual et al., 1982 Casanova et al., 1984). Effective photoreactive conjugation was found to occur after irradiation with UV light at 254 or 310 nm. 

Thyroid hormones exert their effect by binding to nuclear receptors in target organs. Both the thyroid hormones are well absorbed after oral administration. They are conjugated with sulfuric acid in liver and excreted in bile. 

PBBs and PBDEs may also cause toxicity by other mechanisms of action. For example, some PBB congeners can be metabolized to reactive arene oxides (Kohli and Safe 1976 Kohli et al. 1978) that may alkylate critical cellular macromolecules and result in injury. PBDEs may disrupt thyroid hormones by induction of hepatic microsomal UDPGT, which increases the rate of T4 conjugation and excretion, or by mimicking T4 or T3 PBDEs and their hydroxy metabolites are structurally similar to these thyroid hormones which are also hydroxy-halogenated diphenyl ethers (see Section 3.5.2). Clinical interventions designed to interfere with this mechanism or the metabolism of PBBs have yet to be developed. 

Hypothyroidism developed within 2 weeks of rifampicin therapy in these patients and resolved when it was withdrawn. Rifampicin increases thyroxine clearance, possibly by enhancing hepatic thyroxine metabolism and the biliary excretion of iodothyronine conjugates. In healthy volunteers rifampicin reduces circulating thyroid hormone concentrations without affecting thyrotropin, suggesting that rifampicin directly reduces thyroid hormone concentrations. 

The OATP-C, also referred to as liver specific transporter 1 (LST-1) or OATP2, was cloned by number of groups (8,24,25) and was shown to be exclusively expressed in the basolateral membrane of the liver (25). As with OATP-A, OATP-C has broad substrate specificity and transports bile acids (13), sulfate and glucuronide conjugates (25), thyroid hormones (13), and peptides (16), and drugs such as pravastatin (24), methotrexate (26), and rifampin (27). Given its liver-specific expression and broad substrate... 

Thyroid hormone activity is determined predominantly by intracellular concentrations of (free) T3 in the tissues. This T3 bioavailability depends on 1) the secretion of T4 and T3 by the thyroid, 2) the conversion of T4 to T3 outside the thyroid, 3) the metabolic clearance of T3 and 4) exchange of T4 and T3 between plasma and tissues. It is the purpose of this chapter to review recent advancements in the study of the transport and metabolism of thyroid hormone. Especially the role of deiodination, conjugation and tissue uptake mechanisms will be emphasized in the regulation of thyroid hormone action. 

Finnson, K.W., J.M. Mcl eese and J.G. Eales. Deiodination and deconjugation of thyroid hormone conjugates and type I deiodination in liver of rainbow trout, Oncorhynchus mykiss. Gen. Comp. Endocrinol. 115 387-397, 1999. 

Schuur AG, Bergman A, Brouwer A, et al. 1999. Effects of pentachlorophenol and hydroxylated polychlorinated biphenyls on thyroid hormone conjugation in a rat and a human hepatoma cell line. Toxicol in Vitro 13 417-425. 

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