Thallium mediates a rapid chloride/hydroxyl ion exchange through myelin lipid bilayers

We have investigated the effects of several heavy metal cations on the proton and chloride permeabilities of liposomes prepared with endogenous lipids from brain myelin, by monitoring the fluorescence emitted by acridine orange and N-(6-methoxyquinolyl)acetoethyl ester. In addition to Hg2+ and Cu+, nanomolar concentrations of Tl3+, but not Tl+, were able to generate a pH gradient (internally acidic) when an inwardly directed chloride gradient was established. No effect was observed either in the absence of Tl3+ or when Tl3+ was added (a) in the presence of chelating agents, reducing chemicals, or thiol compounds, (b) with identical intra- and extravesicular chloride concentrations, or (c) in the absence of chloride. Furthermore, Tl3+ was able to dissipate a pH gradient across the membrane for identical intra- and extravesicular chloride concentrations and to increase the chloride permeability in response to a pH gradient. All of these results suggest that Tl3+ behaves as a Cl-/OH- exchanger ionophore. Because the kinetics of the process did not vary with alterations of the membrane potential of the liposomes, it was concluded that the reaction is electroneutral, with a Cl-/OH- stoichiometry of 1:1. The results presented could explain some of the toxicological effects, largely unknown to date, of this extremely neurotoxic heavy metal and raise the possibility that thallium could have one of its main neurotoxicological targets in myelin.