Induction of mitochondrial permeability transition by auranofin, a gold(I)-phosphine derivative.
1 Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. 2 Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylphosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. 3 Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. 4 By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. 5 It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase.
Rigobello
Maria Pia
MP
Dipartimento di Chimica Biologica, Università di Padova, Viale G. Colombo 3, Italy.
Scutari
Guido
G
Boscolo
Rita
R
Bindoli
Alberto
A
D000818:Animals; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology*; D001310:Auranofin / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption; D010539:Permeability; D051381:Rats; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism
D018501:Antirheumatic Agents; D007527:Isoenzymes; D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase; D002118:Calcium