Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxR1).
Thioredoxin reductase (TrxR) reduces thioredoxin (Trx), thereby contributing to cellular redox balance, facilitating the synthesis of deoxy-ribose sugars for DNA synthesis, and regulating redox-sensitive gene expression. Auranofin is a gold compound that potently inhibits TrxR. This inhibition is one suspected mechanism of auranofin's therapeutic benefit in the treatment of rheumatoid arthritis. The use of other gold compounds to treat cancer or inflammatory disease may rely on their ability to inhibit TrxR. In the current study, we tested the hypothesis that a variety of gold compounds may inhibit TrxR.


METHODS
We exposed rat-TrxR1 to auranofin, gold sodium thiomalate, sodium aurothiosulfate, triphenyl phosphine gold chloride, or gold acetate, and measured TrxR activity ex vivo. We then compared TrxR1 inhibitory levels of gold compounds to those that inhibited mitochondrial activity of THP1 monocytes and OSC2 epithelial cells, estimated by succinate dehydrogenase activity.


RESULTS
All gold compounds inhibited TrxR1 at concentrations ranging from 5 to 4000 nM (50% inhibitory concentration). The oxidation state of gold did not correlate with inhibitory potency, but ligand configuration was important. Au(I)-phosphine compounds (triphenyl phosphine gold chloride and auranofin) were the most potent inhibitors of TrxR. All TrxR1 inhibitory concentrations were sublethal to mitochondrial activity in both THP1 and OSC2 cells.


CONCLUSIONS
Diverse types of gold compounds may be effective inhibitors of TrxR1 at concentrations that do not suppress cellular mitochondrial function. Inhibition may be optimized to some degree by altering the ligand configuration of the compounds. These results support future study of a variety of Au compounds for therapeutic development as inhibitors of TrxR1.
Omata
Yo
Y
Hokkaido University, Sapporo, Japan.
Folan
Matt
M
Shaw
Melissa
M
Messer
Regina L
RL
Lockwood
Petra E
PE
Hobbs
David
D
Bouillaguet
Serge
S
Sano
Hidehiko
H
Lewis
Jill B
JB
Wataha
John C
JC
D000818:Animals; D001310:Auranofin / Q000633:toxicity; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology*; D004228:Dithionitrobenzoic Acid / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006046:Gold / Q000633:toxicity*; D017612:Gold Compounds / Q000633:toxicity; D006052:Gold Sodium Thiomalate / Q000633:toxicity; D006801:Humans; D009249:NADP / Q000378:metabolism; D051381:Rats; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D017612:Gold Compounds; C038016:gold chloride; D006052:Gold Sodium Thiomalate; D001310:Auranofin; D009249:NADP; D006046:Gold; D004228:Dithionitrobenzoic Acid; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase; C516126:Txnrd1 protein, rat