Aurothioglucose Inhibits Murine Thioredoxin Reductase Activity In Vivo

Abstract

Gold (I)-containing compounds, including aurothioglucose (ATG), are potent in vitro inhibitors of several selenocysteine-containing enzymes. Gold compounds have also been shown to potentiate the virulence of several viruses in mice, including coxsackievirus, implicated as a possible infectious agent in Keshan disease. One possible mechanism by which gold compounds may be increasing the virulence of viral infections in mice is by acting as a selenium antagonist in vivo and inducing oxidative stress. To investigate the possible role of gold compounds in inducing oxidative stress in mice, we assessed the ability of ATG administered in vivo to inhibit the activity of the selenocysteine-containing enzymes thioredoxin reductase (TR) and glutathione peroxidase (GPX1). Doses as low as 0. 025 mg ATG/g body weight caused significant and prolonged inhibition of TR activity in all tissues examined. No such inhibition of GPX1 activity was seen, indicating differential in vivo sensitivity of the enzymes to inhibition by ATG. In liver and heart, some recovery of TR activity was observed after a 7-d period, but no recovery was observed in pancreas or kidney. Because TR is involved in several important cellular redox functions, its inhibition most likely will affect multiple cellular processes. These results indicate that in vivo administration of ATG results in significant and long-lasting inhibition of TR activity. Such inhibition of TR could lead to increased levels of oxidative stress in vivo, thereby increasing the virulence of several viruses including the coxsackievirus.

Glutathione and Glutaredoxin Act as a Backup of Human Thioredoxin Reductase 1 to Reduce Thioredoxin 1 Preventing Cell Death by Aurothioglucose

“…In addition, differently from AF, ATG exhibited very low cytotoxicity on cells (24,25). But indeed, TrxR1 activity in vitro and in vivo was inhibited effectively by ATG (22,26). That is, both ATG and AF inhibit TrxR1 activity in cells, but only AF exhibits cytotoxicity on cells.…”

Interactions of Quinones with Thioredoxin Reductase

“…Furthermore, cytokine functions of extracellular Trx, as well as increased Trx and TrxR levels in some tumor cell lines and in synovial fluid or tissue of patients suffering from rheumatoid arthritis (10,17), argue for targeting of TrxR as a possible therapeutic approach in certain diseases. In fact, TrxR is inactivated by several compounds in clinical use, including 1,3-bis-(2-chloro-ethyl)-1-nitrosourea (BCNU) (18), anticancer platinum compounds (19), antiarthritic gold compounds (20,21), and immunostimulatory dinitrohalobenzenes (22). Modification of TrxR by dinitrohalobenzenes yields covalently linked dinitrophenyl groups that seem to act as mediators between the enzyme-bound FAD and oxygen, thus enhancing the superoxide-producing NADPH oxidase activity of TrxR, while inhibiting the normal function of the enzyme (22).…”

The Anti-rheumatic Gold Salt Aurothiomalate Suppresses Interleukin-1β-induced Hyaluronan Accumulation by Blocking HAS1 Transcription and by Acting as a COX-2 Transcriptional Repressor

“…Gold is toxic to bacteria, and gold has been shown to inhibit thioredoxin reductase as well as glutathione peroxidase activity (47). Gold has also been shown to bind to hexose transport proteins and to thiol pairs on erythrocyte membranes (48).…”