TRANSPORT OF ALPHA-TOCOPHEROL AND ITS DERIVATIVES THROUGH ERYTHROCYTE-MEMBRANES

Purpose, To investigate the transport of alpha-tocopherol (T), tocophe rol succinate (TS) acid tocopherol succinate-3-glucose (a newly synthe tized, less hydrophobic T ester; TSG) through bovine erythrocyte membr anes. Methods, Our experiments were carried out on erythrocytes (obtai ned from heparinized fresh bovine blood), because they represent a sui table model for investigations of membrane transport. Results. T was s hown to reside almost completely in the suspension medium, while the g reater part of TS disappeared from the suspension medium and was mainl y incorporated into erythrocyte membranes. In comparison with T, a lar ger amount of TSG was incorporated into erythrocyte membranes and take n up by cells; however the TSG intracellular accumulation was signific antly lower than that observed with TS. Furthermore, the transport of TS and TSG was partially inhibited by p-chloromercuribenzenesulfonate (which inhibits monocarboxylate uptake; PCMBS) and by maltose (a compe titive inhibitor of glucose transport) respectively, with a concomitan t increase in drug membrane incorporation. No significant change in dr ug transport was observed in the presence of 4,4'-diisothiocyanostilbe ne-2,2'-disulfonate, a selective and irreversible blocker of band 3 pr otein (DIDS). Conclusions. Our results show 1) the existence of large differences in membrane incorporation of T, TS and TSG (very likely ca used by differing abilities to fill spaces in the lipid bilayer) and 2 ) a specific contribution of the monocarboxylate transport protein and of the glucose transport protein in the cellular uptake of TS and TSG , respectively. A tempting suggestion is that the unique cytoprotectiv e properties of TS may be related to the differences in the transmembr ane mobility observed between T and its succinate ester. Furthermore, T conjugation to a monocarboxylate or glycoside moiety could provide s uitable substrates for active membrane transport, thus appearing as a promising pharmaceutical strategy for the improved delivery of tocophe rol derivatives.