Gold in cells The thiolshuttle model

First-generation gold drugs, such as aurothioglucose (1) and disodium aur-othiomalate (2), are injected intramuscularly into patients and from there can interact with cells. It turns out that these usually water soluble and charged species do not enter cells but, rather, bind to the cell membranes via cell surface thiols. In this way, they are able to affect the cell metabolism by interfering with normal cell signalling pathways or starving cells by the inhibition of nutrient uptake.40,41 By contrast, Auranofin (6) (or more precisely its metabolites) is taken up rapidly and extensively by various cells, and Mirabelli et al. postulated a model, known as the thiol-shuttle (or sulphydryl-shuttle), to explain the mechanism of Auranofin transport in and out of cultured macrophage cells.42 Auranofin reaches the cell in its complete form where the drugs encounter sulphydryl-dependent membrane transport proteins (MSH), which populate the cell membrane. Before entering the cell, the thiolate ligand of Auranofin is displaced and remains outside of the cell, whereas the Et3PAu+ moiety binds to the MSH, which transports the cation through the membrane. Once inside the cell, the cation is transferred to proteins and low-molecular-weight thiols, just as in blood, and the phosphine can be oxidized to Et3P=O as described earlier. Whether or not bound to the phosphine, the gold can be taken out of the cell by effectively the same way as it entered it, possibly still bound to an intracellular thiol such as albumin and glutathione (R'SH). Once outside the cell, the gold species again binds to an extracellular thiol, such as albumin, resulting in the formation of an AlbS-Au-SR' complex. This may indeed be the major circulating metabolite after displacement of the original carrier ligands of the drug. The question remains. How is the gold extracted from the above-described 'ball of protein' in order to effect therapeutic use? A proposal gaining acceptance is one that involves the extraction of gold with cyanide at the sites of inflammation.43 46

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