The cellular and molecular pharmacology of auranofin and related gold complexes.

Investigations of the molecular pharmacology of auranofin (AF) and related gold compounds reveal that these gold complexes interact with proteins primarily via sulfhydryl reactions. Moreover, cell association, distribution and efflux of auranofin and related gold complexes can be explained by sequential sulfhydryl exchanges. The rate of the reactions and potential interactions with sulfhydryl groups in different environments vary according to the ligands associated with the gold. Secondary interactions of AF, such as the formation of triethylphosphine oxide and products of lipid oxidation, may also depend upon characteristics of the ligands. The mechanisms of cytotoxicity by which auranofin and closely related compounds affect cells probably include interactions with key membrane structural proteins, protein crosslinks, and effects on key membrane localized enzymes, e.g., phospholipase C. Other cellular effects may include inhibition of DNA polymerase and other enzymatic processes. Resistance to auranofin is mediated by induction of metallothionein in the cells studied. Gold-loaded metallothionein is less stable to proteolysis than cadmium-bound metallothionein, which probably explains the relatively ephemeral nature of resistance to auranofin.