Aurothioglucose

Aurothioglucose (Gold thioglucose) is a well known active-site inhibitor of TrxR1, inhibited TrxR1 activity in HeLa cell cytosol but had no effect on the viability of the cells. IC50 value: Target: TrxR1 in vitro: Trx1 redox state and ROS generation were measured in cells exposed to the TrxR1 inhibitors aurothioglucose (ATG) and monomethylarsonous acid (MMA(III)) and in cells depleted of TrxR1 activity by siRNA knock down [1]. in vivo: Adult mice received a single intratracheal dose of 0.375 μg/g lipopolysaccharide (LPS) 12 h before a single intraperitoneal injection of 25 mg/kg ATG. Control mice received intratracheal and/or intraperitoneal saline. ATG treatment significantly attenuated lung injury, increased lung GCLM expression and GSH levels, and decreased mortality. GSH depletion completely prevented the protective effects of ATG in LPS/hyperoxia-exposed mice [2].

References:
[1]. Watson WH, et al. Thioredoxin reductase-1 knock down does not result in thioredoxin-1 oxidation. Biochem Biophys Res Commun. 2008 Apr 11;368(3):832-6. [2]. Britt RD Jr, et al. The thioredoxin reductase-1 inhibitor aurothioglucose attenuates lung injury and improves survival in a murine model of acute respiratory distress syndrome. Antioxid Redox Signal. 2014 Jun 10;20(17):2681-91.

Glutathione and glutaredoxin act as a backup of human thioredoxin reductase 1 to reduce thioredoxin 1 preventing cell death by aurothioglucose.[Pubmed:22977247]

J Biol Chem. 2012 Nov 2;287(45):38210-9.

Thioredoxin reductase 1 (TrxR1) in cytosol is the only known reductant of oxidized thioredoxin 1 (Trx1) in vivo so far. We and others found that Aurothioglucose (ATG), a well known active-site inhibitor of TrxR1, inhibited TrxR1 activity in HeLa cell cytosol but had no effect on the viability of the cells. Using a redox Western blot analysis, no change was observed in redox state of Trx1, which was mainly fully reduced with five sulfhydryl groups. In contrast, auranofin killed cells and oxidized Trx1, also targeting mitochondrial TrxR2 and Trx2. Combining ATG with ebselen gave a strong synergistic effect, leading to Trx1 oxidation, reactive oxygen species accumulation, and cell death. We hypothesized that there should exist a backup system to reduce Trx1 when only TrxR1 activity was lost. Our results showed that physiological concentrations of glutathione, NADPH, and glutathione reductase reduced Trx1 in vitro and that the reaction was strongly stimulated by glutaredoxin1. Simultaneous depletion of TrxR activity by ATG and glutathione by buthionine sulfoximine led to overoxidation of Trx1 and loss of HeLa cell viability. In conclusion, the glutaredoxin system and glutathione have a backup role to keep Trx1 reduced in cells with loss of TrxR1 activity. Monitoring the redox state of Trx1 shows that cell death occurs when Trx1 is oxidized, followed by general protein oxidation catalyzed by the disulfide form of thioredoxin.

The thioredoxin reductase-1 inhibitor aurothioglucose attenuates lung injury and improves survival in a murine model of acute respiratory distress syndrome.[Pubmed:24295151]

Antioxid Redox Signal. 2014 Jun 10;20(17):2681-91.

AIMS: Inflammation and oxygen toxicity increase free radical production and contribute to the development of acute respiratory distress syndrome (ARDS), which is a significant cause of morbidity and mortality in intensive care patients. We have previously reported increased glutathione (GSH) levels in lung epithelial cells in vitro and attenuated adult murine hyperoxic lung injury in vivo after pharmacological thioredoxin reductase-1 (TrxR1) inhibition. Using a murine ARDS model, we tested the hypothesis that Aurothioglucose (ATG) treatment increases pulmonary GSH levels, attenuates lung injury, and decreases mortality in a GSH-dependent manner. RESULTS: Adult mice received a single intratracheal dose of 0.375 mug/g lipopolysaccharide (LPS) 12 h before a single intraperitoneal injection of 25 mg/kg ATG. Control mice received intratracheal and/or intraperitoneal saline. Mice were then exposed to room air or hyperoxia (>95% O2). Lung injury was assessed by bronchoalveolar lavage protein concentrations. Expression of glutamate-cysteine ligase modifier subunit (GCLM), GSH, cytokines, and chemokines was determined. Exposure to LPS/hyperoxia induced inflammation and lung injury. ATG treatment significantly attenuated lung injury, increased lung GCLM expression and GSH levels, and decreased mortality. GSH depletion completely prevented the protective effects of ATG in LPS/hyperoxia-exposed mice. INNOVATION: ATG treatment significantly attenuates lung injury and enhances survival in a clinically relevant murine model of ARDS. The protective effects of ATG are GSH dependent. CONCLUSION: Augmentation of GSH systems by TrxR1 inhibition could represent a promising therapeutic approach to attenuate oxidant-mediated lung injury and improve patient outcomes.

The progression of neuronal, myelin, astrocytic, and immunological changes in the rat brain following exposure to aurothioglucose.[Pubmed:12213313]

Brain Res. 2002 Sep 13;949(1-2):171-7.

Aurothioglucose (ATG) is presently employed both by clinicians in the treatment of advanced rheumatoid arthritis and by neuroscience researchers to generate lesions around the circumventricular organs (CVOs) of rodent brains, resulting in obese animals. Although the existence of such lesions is well documented, there is relatively little information concerning the changes over time of the different cell types in the regions surrounding the CVOs. To address this question, specific markers allowing identification of four distinct cellular populations were used to characterize respective changes over time. Generally, regions adjacent to the CVOs were more vulnerable than the CVOs themselves, while more caudal structures were more frequently lesioned than more anterior CVO regions. Vascular and glial cells appeared to be the initial targets of ATG, while neuronal cell death occurred subsequent to the inflammatory response. The results of this study help resolve the mechanism of ATG toxicity as reflected by a cascade of pathologies that is consistent with disparate cell types exhibiting specific changes at specific times.

Parenteral gold preparations. Efficacy and safety of therapy after switching from aurothioglucose to aurothiomalate.[Pubmed:15940762]

J Rheumatol. 2005 Jun;32(6):1026-30.

OBJECTIVE: For reasons of insufficient quality of the raw material, Aurothioglucose was withdrawn from the Dutch market at the end of 2001. Aurothiomalate became available as an alternative preparation. We followed a cohort of patients during the first year after switching from Aurothioglucose to aurothiomalate to study efficacy and tolerability. METHODS: Patients were observed at baseline and at 3 and 12 months after switching. At each visit, data on adverse drug reactions (ADR), withdrawal, and disease activity were collected. RESULTS: In total 120 patients were included [age 63(SD 15) yrs, 68% female, 93% with rheumatoid arthritis, duration of disease 15 (SD 9) years, 82% IgM rheumatoid factor-positive, with 9 (SD 9, range 0.1-45) yrs of previous Aurothioglucose therapy]. Nineteen patients (16%) reported an ADR taking aurothiomalate not previously experienced with Aurothioglucose, the most frequently reported being pruritus, dermatitis/stomatitis, and chrysiasis/hyperpigmentation. Twenty-nine patients (24%) withdrew from aurothiomalate within 12 months of followup for reasons of inefficacy (14%), ADR (7%), or disease in state of remission (3%). Kaplan-Meier estimates show aurothiomalate survival rates of 78.5% after 12 months. No statistically significant differences between the disease activity indicators during followup visits compared with the baseline visit were detected for the patients continuing aurothiomalate. CONCLUSION: Within the first 12 months after switching from Aurothioglucose, 24% of patients withdrew from aurothiomalate. Sixteen percent of patients reported novel ADR. For the population continuing to take aurothiomalate no clinically relevant changes in disease activity were recorded after switching.

Aurothioglucose (Gold thioglucose) is a well known active-site inhibitor of TrxR1, inhibited TrxR1 activity in HeLa cell cytosol but had no effect on the viability of the cells.

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