Gold-induced reactive oxygen species (ROS) do not mediate suppression of monocytic mitochondrial or secretory function.
The toxicity of anti-rheumatic gold compounds has limited their use and development, yet both the toxicological and therapeutic actions of these compounds remain unclear. In the current study, we tested the hypothesis that intracellular reactive oxygen species (ROS) induced by Au(I) or Au(III) compounds mediate their ability to suppress mitochondrial activity.


METHODS
Human THP1 monocytes were exposed to HAuCl(4) x 3H(2)O (Au(III)), or the anti-rheumatic compounds auranofin (AF) or gold sodium thiomalate (GSTM) for 6-72 h, after which mitochondrial activity (succinate dehydrogenase) was measured. To assess the role of cellular redox status as a mediator of mitochondrial suppression, monocytes were pre-treated with a pro-oxidant (t-butyl hydroquinone, t-BHQ) or antioxidant (N-acetyl cysteine, NAC ). ROS levels were measured 0-24h post-gold addition to determine their role as mediators of mitochondrial activity suppression.


RESULTS
AF was the most potent inhibitor of mitochondrial activity, followed by Au(III) and GSTM. Only Au(III) induced intracellular ROS; no ROS formation was observed in response to AF or GSTM exposure. Although anti- and pro-oxidants had some effects on mitochondrial suppression of Au compounds, collectively the data do not support redox effects or ROS formation as major mediators of Au-compound mitochondrial suppression.


CONCLUSIONS
Our results do not indicate that ROS and redox effects play major roles in mediating the cytotoxicity of AF, GSTM or Au(III).
Omata
Yo
Y
Hokkaido University, Sapporo, Japan.
Lewis
Jill B
JB
Lockwood
Petra E
PE
Tseng
Wan Y
WY
Messer
Regina L
RL
Bouillaguet
Serge
S
Wataha
John C
JC
D001310:Auranofin / Q000633:toxicity; D002478:Cells, Cultured; D017612:Gold Compounds / Q000633:toxicity*; D006052:Gold Sodium Thiomalate / Q000633:toxicity; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017612:Gold Compounds; D017382:Reactive Oxygen Species; C038016:gold chloride; D006052:Gold Sodium Thiomalate; D001310:Auranofin