Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxR1)

Yo Omata, Matt Folan, Melissa Shaw, Regina L. Messer, Petra E. Lockwood, David Hobbs, Serge Bouillaguet, Hidehiko Sano, Jill B. Lewis, John C. Wataha

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)882-890
Number of pages9
JournalToxicology in Vitro
Volume20
Issue number6
DOIs
StatePublished - Sep 1 2006

Keywords

  • Gold compounds
  • Metals
  • Mitochondrial activity
  • Oxidative stress
  • Redox
  • Thioredoxin

ASJC Scopus subject areas

  • Toxicology

Fingerprint Dive into the research topics of 'Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxR1)'. Together they form a unique fingerprint.

  • Cite this

    Omata, Y., Folan, M., Shaw, M., Messer, R. L., Lockwood, P. E., Hobbs, D., Bouillaguet, S., Sano, H., Lewis, J. B., & Wataha, J. C. (2006). Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxR1). Toxicology in Vitro, 20(6), 882-890. https://doi.org/10.1016/j.tiv.2006.01.012