Species-specific lipophilicity of thyroid hormones and their precursors in view of their membrane transport properties

[Display omitted] ► The species-specific lipophilicity of thyroid hormones and their precursors were determined. ► Contributions of the zwitterionic forms to the overall lipophilicity are higher than those of the non-charged ones. ► At physiological pH thyroid hormones are strongly amphipathic. ► The results were interpreted in terms of their membrane transport properties. A total of 30 species-specific partition coefficients of three thyroid hormones (thyroxine, liothyronine, reverse liothyronine) and their two biological precursors (monoiodotyrosine, diiodotyrosine) are presented. The molecules were studied using combined methods of microspeciation and lipophilicity. Microspeciation was carried out by 1H NMR-pH and UV-pH titration techniques on the title compounds and their auxiliary derivatives of reduced complexity. Partition of some of the individual microspecies was mimicked by model compounds of the closest possible similarity, then correction factors were determined and introduced. Our data show that the iodinated aromatic ring system is the definitive structural element that fundamentally determines the lipophilicity of thyroid hormones, whereas the protonation state of the aliphatic part plays a role of secondary importance. On the other hand, the lipophilicity of the precursors is highly influenced by the protonation state due to the relative lack of overwhelmingly lipophilic moieties. The different logp values of the positional isomers liothyronine and reverse liothyronine represent the importance of steric and electronic factors in lipophilicity. Our investigations provided clear indication that overall partition, the best membrane transport – predicting physico-chemical parameter depends collectively on the site-specific basicity and species-specific partition coefficient. At physiological pH these biomolecules are strongly amphipathic due to the lipophilic aromatic rings and hydrophilic amino acid side chains which can well be the reason why thyroid hormones cannot cross membranes by passive diffusion and they are constituents of biological membranes. The lipophilicity profile of thyroid hormones and their precursors are calculated and depicted in terms of species-specific lipophilicities over the entire pH range.