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.