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

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

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

Omata, Yo; Folan, Matt; Shaw, Melissa et al.

Toxicology in Vitro, 2006, 20(6), 882-890

Permalink : https://hdl.handle.net/2115/14470

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アクセス権	open access
URI	https://hdl.handle.net/2115/14470
タイトル	Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxR1)
著者	Omata, Yo ; Folan, Matt ; Shaw, Melissa ; Messer, Regina L. ; Lockwood, Petra E. ; Hobbs, David ; Bouillaguet, Serge ; Sano, Hidehiko ; Lewis, Jill B. ; Wataha, John C.
著者名 Omata, Yo 小俣, 葉
著者名 Folan, Matt
著者名 Shaw, Melissa
著者名 Messer, Regina L.
著者名 Lockwood, Petra E.
著者名 Hobbs, David
著者名 Bouillaguet, Serge
e-Rad_Researcher 90205998 著者名 Sano, Hidehiko 佐野, 英彦
著者名 Lewis, Jill B.
著者名 Wataha, John C.
言語	英語
キーワード	metals
	redox
	oxidative stress
	mitochondrial activity
	thioredoxin
	gold compounds
発行日	2006-09
出版者	Elsevier
収録物名	Toxicology in Vitro
巻(号)	20(6)
ページ	882-890
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
PISSN	0887-2333
関連情報	PMID 16510263
関連情報	URI http://www.sciencedirect.com/science/journal/08872333
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1016/j.tiv.2006.01.012