Rigobello, Maria Pia and Messori, Luigi and Marcon, Giordana and Cinellu, Maria Agostina and Bragadin, Marcantonio and Folda, Alessandra and Scutari, Guido and Bindoli, Alberto (2004) Gold complexes inhibit mitochondrial thioredoxin reductase: consequences on mitochondrial functions. Journal of Inorganic Biochemistry, Vol. 98 (10), p. 1634-1641. ISSN 0162-0134. Article.
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The effects of gold(I) complexes (auranofin, triethylphosphine gold and aurothiomalate), gold(III) complexes ([Au(2,2′-diethylendiamine)Cl]Cl2, [(Au(2-(1,1-dimethylbenzyl)-pyridine) (CH3COO)2], [Au(6-(1,1-dimethylbenzyl)-2,2′-bipyridine)(OH)](PF6), [Au(bipydmb-H)(2,6-xylidine)](PF6)), metal ions (zinc and cadmium acetate) and metal complexes (cisplatin, zinc pyrithione and tributyltin) on mitochondrial thioredoxin reductase and mitochondrial functions have been examined. Both gold(I) and gold(III) complexes are extremely efficient inhibitors of thioredoxin reductase showing IC50 ranging from 0.020 to 1.42 μM while metal ions and complexes not containing gold are less effective, exhibiting IC50 going from 11.8 to 76.0 μM. At variance with thioredoxin reductase, auranofin is completely ineffective in inhibiting glutathione peroxidase and glutathione reductase, while gold(III) compounds show some effect on glutathione peroxidase. The mitochondrial respiratory chain is scarcely affected by gold compounds while the other metal complexes and metal ions, in particular zinc ion and zinc pyrithione, show a more marked inhibitory effect that is reflected on a rapid induction of membrane potential decrease that precedes swelling. Therefore, differently from gold compounds, the various metal ions and metal complexes exert their effect on different targets indicating a lower specificity. It is concluded that gold compounds are highly specific inhibitors of mitochondrial thioredoxin reductase and this action influences other functions such as membrane permeability properties. Metal ions and metal complexes markedly inhibit the activity of thioredoxin reductase although to an extent lower than that of gold compounds. They also inhibit mitochondrial respiration, decrease membrane potential and, finally, induce swelling.
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