Tóth Gergo, Noszál Béla
Semmelweis Egyetem, Gyógyszerészi Kémiai Intézet, Magyar Tudományos Akadémia Kábító- és Doppingszer-tudomdányi Társult Kutatócsoport, Budapest, Hogyes Endre utca 9.
Acta Pharm Hung. 2013;83(2):35-45.
This paper and the following one (see the next issue of Acta Pharmaceutica Hungarica) survey the biological roles and the related site-specific physico-chemical parameters (basicity and lipophilicity) of the presently known thyroid hormones (thyroxine, liothyronine and reverse liothyronine) and their biological precursors (monoiodotyrosine and diiodotyrosine). Here the literature of the thyroid hormone biochemistry, biosynthesis, plasma- and membrane transport is summarized, focusing on the pH-dependent processes. Biosyntheses of the thyroid hormones take place by oxidative coupling of two iodotyrosine residues catalyzed by thyreoperoxidase in thyreoglobulin. The protonation state of the precursors, especially that of the phenolic OH is crucial for the biosynthesis, since anionic iodotyrosine residues can only be coupled in the thyroid hormone biosyntheses. In the blood more than 99% of the circulating thyroid hormone is bound to plasma proteins among which the thyroxine-binding globulin and transthyretin are crucial. The amphiphilic character of the hormones is assumed to be the reason why their membrane transport is an energy-dependent, transport-mediated process, in which the organic anion transporter family, mainly OATP1C1, and the amino acid transporters, such as MCT8 play important roles. Liothyronine is the biologically active hormone; it binds the thyroid hormone receptor, a type of nuclear receptor. There are two major thyroid hormone receptor (TR) isoforms, alfa (TRalpha) and beta (TRbeta). The activation of the TRalpha is associated with modifications in cardiac behavior, while activation of the TRbeta is associated with increasing metabolic rates, resulting in weight loss and reduction of blood plasma lipid levels. The affinity of the thyroid hormones for different proteins depends on the ionization state of the ligands. The site-specific physico-chemical characterization of the thyroid hormones is of fundamental importance to understand their (patho)physiological behavior and also, to influence their therapeutic properties at the molecular level.
本文及后续一篇文章（见下一期《匈牙利药学学报》）综述了目前已知的甲状腺激素（甲状腺素、三碘甲状腺原氨酸和反式三碘甲状腺原氨酸）及其生物前体（一碘酪氨酸和二碘酪氨酸）的生物学作用以及相关的位点特异性物理化学参数（碱度和亲脂性）。这里总结了甲状腺激素生物化学、生物合成、血浆和膜转运方面的文献，重点关注pH依赖性过程。甲状腺激素的生物合成是通过甲状腺球蛋白中甲状腺过氧化物酶催化的两个碘酪氨酸残基的氧化偶联进行的。前体的质子化状态，尤其是酚羟基的质子化状态对于生物合成至关重要，因为阴离子碘酪氨酸残基只能在甲状腺激素生物合成中偶联。在血液中，超过99%的循环甲状腺激素与血浆蛋白结合，其中甲状腺素结合球蛋白和转甲状腺素蛋白至关重要。激素的两亲性被认为是其膜转运是能量依赖性、转运介导过程的原因，在这个过程中，有机阴离子转运体家族，主要是OATP1C1，以及氨基酸转运体，如MCT8发挥重要作用。三碘甲状腺原氨酸是具有生物活性的激素；它与一种核受体——甲状腺激素受体结合。有两种主要的甲状腺激素受体（TR）亚型，α（TRα）和β（TRβ）。TRα的激活与心脏行为的改变有关，而TRβ的激活与代谢率增加有关，导致体重减轻和血浆脂质水平降低。甲状腺激素对不同蛋白质的亲和力取决于配体的电离状态。甲状腺激素的位点特异性物理化学特征对于理解其（病理）生理行为以及在分子水平上影响其治疗特性至关重要。
