Pyrithione and 8-hydroxyquinolines transport lead across erythrocyte membranes

Acute and chronic lead poisoning remains a significant health problem. Although chelating agents can bind to plasma lead, they cannot cross cell membranes where the total body lead burden resides, and are thus inefficient at reducing the total body lead burden. Recently, calcium and sodium ionophores have been shown to transport lead across cell membranes providing a novel method for reducing total body lead stores. We recently found that clioquinol, an 8-hydroxyquinoline derivative, can act as a zinc ionophore. We postulated that zinc ionophores might also be able to transport lead across biological membranes. To study this, we loaded lead in vitro into human erythrocytes and then studied the ability of zinc ionophores to transport lead into the extracellular space, where it was trapped with a lead chelator. Using inductively coupled plasma mass spectrometry (ICP-MS), we found that several 8-hydroxyquinoline derivatives, as well as the zinc and sodium salts of pyrithione (N-hydroxypyridine-2-thione), reduced erythrocyte lead content. The water-soluble compound, sodium pyrithione, was able to reduce lead in citrated whole blood, without partitioning into the erythrocytes. These results indicate that two classes of zinc ionophores can transport lead across a biological membrane, and they confirm that these ionophores are not cation-specific. Lead ionophores may prove useful in mobilizing lead into the extracellular space, thereby improving the efficacy of chelation therapy, in vivo or ex vivo.