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PubMed1984

Interaction of the human leukocyte proteinases elastase and cathepsin G with gold, silver and copper compounds.

Gold thiomalate and the corresponding silver and copper derivatives were investigated as inhibitors of the human leukocyte proteinases elastase and cathepsin G. The kinetic inhibition mechanism for gold- and silver thiomalate is of the hyperbolic non-competitive type with both enzymes and the inhibitory efficiency of the metals increases in the order Cu less than Ag less than Au. On the contrary, D-penicillamine derivatives of the three metals do not influence at all the activity of the two proteinases. Although gold thiomalate is the most efficient of the investigated metal compounds (Ki = 33 microM and 25 microM for elastase and cathepsin G, respectively), the hyperbolic nature of the inhibition imposes a serious limit to its practical usefulness since the maximum inhibitory action on both enzymes is about 40%. We suggest that, in order to act as inhibitor, a copper, silver or gold compound must be able to easily transfer the metal to the enzyme.

Cathepsin G↗
PubMed1996

Species differences in the renal toxicity of the antiarthritic drug, gold sodium thiomalate.

Two gold compounds, gold sodium thiomalate (AuTM) and auranofin, are presently in clinical use in therapy of rheumatoid arthritis. In these studies, AuTM administered to Sprague-Dawley rats and three strains of mice, Swiss-Webster, C3H/HeJ, and DBA/2J, were studied with regard to its effect on liver and renal monooxygenases, metallothionein contents, and serum levels of alanine aminotransferase and urea nitrogen. These effects of AuTM were compared to those of cadmium, since the latter metal has exhibited tissue and species differences in the induction of metallothionein. Benzo(a)pyrene hydroxylase and benzphetamine N-demethylase activities were not altered by AuTM in livers of rats and the three strains of mice. Benzo(a)pyrene hydroxylase activity was significantly decreased in rat kidney, whereas this enzyme activity was not affected in the kidneys of mice. In rats, AuTM caused a sevenfold induction in liver metallothionein, while in mice, liver metallothionein was induced twofold in Swiss-Webster mice and about fivefold in the inbred strains. AuTM caused minimal changes in renal metallothionein contents in the three strains of mice studied. Serum alanine amino-transferase, an indicator of hepatotoxicity, was not altered by AuTM in rats and mice studied. Blood urea nitrogen, an indicator of kidney dysfunction, was increased threefold in rats, but not in AuTM-treated mice. These data demonstrate that AuTM, a nephrotoxic agent in rats and humans, showed no nephrotoxic effects in the mouse strains studied here.

Alanine Transaminase↗
PubMed1990

The effect of gold sodium thiomalate and auranofin on lipopolysaccharide-induced interleukin-1 production by blood monocytes in vitro: variation in healthy subjects and patients with arthritis.

The anti-rheumatic gold compounds gold sodium thiomalate (GST) and auranofin (AF) have variable and often unpredictable effects in patients treated for arthritis. As inhibition of interleukin-1 (IL-1) production may be an important effect of these drugs, we investigated their effect on IL-1 production by lipopolysaccharide (LPS) stimulated monocytes in a serum-free, non-adherent culture system. A bi-modal effect was observed: low concentrations (GST 10-250 ng/ml and AF 1-100 ng/ml) potentiated IL-1 production, and higher concentrations (GST 200-1000 ng/ml and AF10-500 ng/ml) inhibited it. This bi-modal effect was observed for both secreted and cell-associated IL-1 activity with the exception that GST failed to inhibit cell-associated IL-1 generation. The potentiating effect was dependent on the continuous presence of gold for at least the first few hours after LPS stimulation. The inhibitory effect of GST was dependent on its presence after LPS stimulation while that of AF was evident even if cells were pretreated with AF and washed before exposure to LPS. There was considerable individual variation in IL-1 production in response to LPS as well as in the effects of gold on cells from both healthy individuals and patients with arthritis. There was also some overlap in the range of concentrations of gold that potentiated and inhibited IL-1 production, and there was relative insensitivity to the inhibitory effects of gold in certain individuals. These results may explain some of the variability in the response of patients to chrysotherapy and support further studies to see if these in vitro effects might predict clinical response to gold.

Arthritis↗
PubMed1991

The effect of slow-acting anti-rheumatic drugs (SAARDs) and combinations of SAARDs on monokine production in vitro.

The mode of action of slow-acting anti-rheumatic drugs (SAARDs) is complex but may often include effects on cytokine (interleukin-1, IL-1, and tumour necrosis factor, TNF) production by monocytes/macrophages. Different SAARDs may have variable effects on cytokine production in vitro depending on the concentration of drug, the presence of other SAARDs and individual variation. The gold compounds gold sodium thiomalate (GST) and auranofin (AF) had a bimodal effect on cytokine production. High concentrations of GST (greater than 1 microgram/ml) weakly inhibited IL-1-beta secretion (without affecting IL-1-alpha or TNF secretion and without affecting cell-associated IL-1-alpha and IL-1-beta accumulation), and although AF (greater than 100 ng/ml) inhibited cytokine production it did so at concentrations near to the toxic range for the drug (greater than 200 ng/ml). GST and AF when used in combination inhibited cytokine production in a synergistic manner even at concentrations that would potentiate cytokine production if used individually. Hydroxychloroquine (HCQ) and sulfasalazine (SAP) were two other inhibitory SAARDs which acted synergistically in combination. Combination of HCQ and SAP with gold drugs gave variable results. D-penicillamine (D-pen) and methotrexate (MTX) were two SAARDs that generally did not affect cytokine production individually or in combination with other SAARDs. These results suggest that combination SAARD therapy may more effectively target excessive cytokine production, which is a hallmark of rheumatoid arthritis.

Anti-Inflammatory Agents↗
PubMed1989

Pharmacologic modulation of TNF production by endotoxin stimulated macrophages: in vitro and in vivo effects of auranofin and other chrysotherapeutic compounds.

The gold compounds, auranofin, sodium aurothiomalate, and triethyl gold phosphine have been demonstrated to inhibit various effector functions associated with monocyte-macrophage populations. Incubation of human peripheral blood monocytes and murine peritoneal macrophages with auranofin or triethyl gold phosphine inhibited TNF production in lipopolysaccharide [LPS] stimulated murine peritoneal macrophages. The inhibitory effect of auranofin and triethyl gold phosphine on LPS stimulated monokine production was reversible when these compounds were incubated with macrophage cultures at concentrations between 0.1-0.5 micrograms/ml. These compounds also inhibited both TNF and IL-1 production by human peripheral blood monocytes. Sodium aurothiomalate at these concentrations had no inhibitory effect on TNF or IL-1 production. Auranofin and triethyl gold phosphine also inhibited TNF production in vivo when compounds were administered orally or intraperitoneally 2 hours prior to a lethal dose of endotoxin. Serum TNF levels from Balb/c mice were significantly reduced when animals were predosed with 1-25 mg/kg of auranofin. The data suggest that the inhibition of TNF production by activated macrophages may contribute to the therapeutic role of gold compounds in the management of chronic inflammatory disease.

Animals↗
PubMed1985

Effects of anti-inflammatory and anti-rheumatic drugs on the activities of purified and membrane-bound Na+/K+ adenosine triphosphatase.

We have examined the effects of anti-inflammatory and anti-rheumatic drugs on membrane-bound and purified Na+/K+-ATPase activity in vitro. Only the gold-containing compounds (gold sodium thiomalate and auranofin) were found to inhibit the enzyme activity in a dose-dependent manner. Sodium thiomalate and triethylphosphine, the ligand compounds for gold sodium thiomalate and auranofin, respectively, had no effect on ATPase activity. The antagonistic properties was abolished by preincubation of the gold compounds with dithiothreitol. Lineweaver-Burke analysis of the inhibitions of purified ATPase by the gold compounds was found to follow uncompetitive kinetics. Inhibition of ATPase by gold may cause disruption of transmembrane cation transport and thus result in impairment of several metabolic processes and cellular functions.

Animals↗
PubMed2000

Applications of gold cluster compounds in immunocytochemistry and correlative microscopy: comparison with colloidal gold.

In this review, we discuss the immunocytochemical literature with respect to a comparison between conventional colloidal gold and gold cluster compounds as immunoprobes. The relative advantages and disadvantages of each of these types of particle for immunocytochemical applications are discussed. We present results from our own laboratories and those of others on the comparison of these immunoprobes in selected experimental situations. These results show the use of gold cluster compounds at both light and electron microscope levels. At the ultrastructural level, gold cluster compounds have been used in pre-embedding labelling of cultured cells, and for labelling of ultrathin cryosections and freeze-fracture preparations. Recently, fluorescently tagged gold cluster compounds have become available. Using ultrathin cryosections of human neutrophils as a model system, we demonstrate that a single immunoprobe (i.e. a fluorescently tagged gold cluster compound) is a robust probe for correlative fluorescence and electron microscopy.

Gold Colloid↗
PubMed2004

Influence of metalation on the morphologies of poly(ethylene oxide)-block-poly(4-vinylpyridine) block copolymer micelles.

Micellization of a poly(ethylene oxide)-block-poly(4-vinylpyridine) (PEO45-b-P4VP28) copolymer in water during metalation (incorporation of gold compounds and gold nanoparticle formation) with three types of gold compounds, NaAuCl4, HAuCl4, and AuCl3, was studied using dynamic light scattering (DLS) and transmission electron microscopy (TEM). The transformations of the PEO45-b-P4VP28 block copolymer micelles in water were found to depend on a number of parameters including the thermal history of the as-prepared block copolymer, the type of the metal compound, and the metal loading. For the HAuCl4-filled PE045-b-P4VP28 micelles, the subsequent reduction with hydrazine hydrate results in a significant fraction of rodlike micelles, suggesting that slow nucleation (confirmed by the formation of the large gold nanoparticles) and facilitated migration of gold ions yields the ideal conditions for sphere-to-rod micellar transition.

Journal Article↗
PubMed1993

Adverse immune reactions to gold in rheumatoid arthritis: lack of skin reactivity.

Adverse immune reactions develop in up to 30% of patients treated with gold compounds. However, sensitization to gold(I) drugs is rarely demonstrated by in vivo or in vitro testing. Recent data from a mouse model provides evidence that gold(I) is oxidized to gold(III) before T cells are sensitized. To study the diagnostic value of skin tests, patch testing with various gold compounds - including gold(I) and gold(III) - was performed in 50 patients with rheumatoid arthritis treated with gold(I) drugs. Positive patch test reactions to either gold(I) or gold(III) compounds were not detected. In contrast, the lymphocyte transformation test (LTT) revealed a gold(III)-induced response in one of the 7 patients being tested. We conclude that patch testing fails to indicate T cell sensitization to gold(I) drugs in rheumatoid arthritis patients. The in vitro response to gold(III) obtained by LTT supports the hypothesis that biooxidation of gold(I) compounds may play a crucial role for sensitization.

Arthritis, Rheumatoid↗
PubMed1989

Effects of gold coordination complexes on neutrophil function are mediated via inhibition of protein kinase C.

Previous studies have shown that the gold compounds auranofin (AUR) and gold sodium thiomalate (GST) inhibit responses of various cells and tissues. We found that superoxide anion generation induced in human neutrophils by the chemotactic tripeptide fmet-leu-phe (1 microM), fluoride (18 mM), or phorbol myristate acetate (PMA, 100 nM) was inhibited by pretreatment of cells with 5-100 microM AUR. The extent of inhibition was dependent on AUR concentration and duration of the preincubation. GST was much less potent, inasmuch as only weak effects were observed at 5 times higher concentrations. The ineffectiveness of GST was attributed to its slower rate of penetration into cells, compared with AUR. The finding that mobilization of internal Ca2+ stores was not blocked in AUR-treated cells suggests that phospholipase C-mediated hydrolysis of polyphosphoinositides to inositol 1,4,5-trisphosphate was not inhibited by the drug. Because PMA is known to mimic the action of diacylglycerol in activating protein kinase C (PKC), we investigated the possibility that gold compounds might be interfering with signal transduction at this level. Enzymatic assays indicated that both gold compounds reduced the level of PKC activity associated with the cytosol; however, translocation of PKC to the plasma membrane was not found. Immunoblot analyses carried out with polyclonal anti-PKC antisera revealed that the gold compounds did not cause degradation of PKC or increase translocation to the membrane. Further studies indicated that enhanced endogenous protein phosphorylation resulting from PMA stimulation was attenuated in cells co-treated with AUR. Finally, in vitro enzymatic assays showed that both AUR and GST inhibited partially purified PKC in a concentration-dependent manner. It is suggested that modulation of PKC represents a mechanism of action of gold coordination complexes at the cellular level.

Auranofin↗
PubMed2006

Gold(III) compound is a novel chemocytotoxic agent for hepatocellular carcinoma.

Recently, a series of gold(III) meso-tetraarylporphyrins that are stable against demetallation in physiological conditions have been synthesized. In the present study, the antitumor effects of one of these compounds, gold(III) meso-tetraarylporphyrin 1a (gold-1a) was investigated in an orthotopic rat hepatocellular carcinoma (HCC) model as well as using a HCC cell line. The rat HCC model was induced by injection of rat hepatoma cells, McA-RH7777, into the left lobe of the liver. Seven days after tumor cell inoculation, gold-1a was injected directly into the tumor nodule at different doses, followed by the same doses via intraperitoneal injection twice a week. Gold-1a administration significantly prolonged the survival of HCC-bearing rats. Importantly, gold-1a induced necrosis as well as apoptosis in the tumor tissues, but not in the normal liver tissues. Furthermore, gold-1a treatment neither caused significant drop in body weight of the rats nor affected plasma aspartate aminotransferase level. In the in vitro studies, we observed that gold-1a treatment inhibited the proliferation of McA-RH7777 cells. Gold-1a upregulated genes that increase apoptosis, stabilize p53, decrease proliferation and downregulated genes playing roles in angiogenesis, invasion, and metabolism, as demonstrated by microarray. In particular, the compound upregulated 2 members of the growth arrest and DNA damage (Gadd) inducible gene family, Gadd34 and Gadd153. Suppression of Gadd34 and Gadd153 in McA-RH7777 cells by small hairpin RNA reduced the gold-1a-induced apoptosis and growth inhibition, indicating that gold-1a mediated its effects via upregulation of Gadd34 and Gadd153. Results from our study demonstrated that gold-1a might be a novel promising chemocytotoxic agent for treating HCC.

Alanine Transaminase↗
PubMed1984

Auranofin.

It has been widely accepted for a number of years that chrysotherapy is a valuable therapeutic agent in the treatment of progressive rheumatoid disease. This therapeutic benefit has, to some extent, been offset by the potential toxicity associated with gold compounds. The development of a gold compound with a greater therapeutic to toxicity ratio would be of considerable interest and benefit, to both patients and physicians. Initial studies with auranofin suggested that this compound was a reliably absorbed agent and that its use would avoid regular gold thiol injections. Its initial therapeutic profile was considered to be similar to that of injectable gold compounds, but with a significantly greater safety margin. The further information that has accrued from the clinical studies reported so far would tend to support these early suggestions in that auranofin has compared very favourably with gold thiols and other disease-remittive agents and that the prevalence of side effects requiring withdrawal of therapy has been approximately 25-30 per cent less. In addition, the reasons for withdrawal have often been less potentially serious side effects, notably nephrotoxicity and haematological reactions. In a review of over 3000 patients treated with auranofin, compared to 465 patients treated with injectable gold, the frequency of withdrawal from studies due to inefficacy of auranofin was approximately two to three times higher than with the gold thiols. It would appear, therefore, that in those patients continuing on therapy, auranofin is similar to injectable gold, but that a higher proportion of patients will fail to get a response within three to six months to the therapy. This potential lack of therapeutic effect is offset by the increased safety margin. In time, it is possible that auranofin will be accepted for earlier treatment in the course of rheumatoid disease than perhaps would normally have been considered. The in vivo and in vitro studies of auranofin on its mechanism of action are of considerable interest. They provide theoretical and valuable information on the mechanism of action of gold compounds and the cellular functions and interactions which may be involved in the pathogenesis of rheumatoid disease. It is interesting to note that auranofin appears to be more potent and have different effects than gold thiols, despite the fact that in terms of clinical therapeutic profile the compounds are similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2002

Cytotoxicity of ingredients of various dental materials and related compounds in L2- and A549 cells.

Various ingredients of dental materials and related compounds were tested for cytotoxicity in two alveolar epithelial cell lines (L2 and A549 cells). Release of lactate dehydrogenase (LDH) from cells was measured after incubation with the test substances for time intervals up to 48 h and expressed as percentage of total LDH content of lysed cells. Furthermore, the glutathione content of cells was determined in the nonmalignant L2 cells. Additionally, cell viability was assessed by microscopic examination. The highest cytotoxicity was observed with mercury compounds (methylmercuric chloride and mercury dichloride) in the range of 5-20 micromol/l. The composite components 2-hydroxyethylmethacrylate (HEMA) and triethleneglycoldimethacrylate (TEGDMA) showed time- and concentration-dependent effects of cytotoxicity at high concentrations (about 1-5 mmol/l). A time dependence for GSH decrease was mainly found for the composite components up to 12 h of cellular exposure. L2 cells were more sensitive to both mercury and composite compounds than A549 cells. Gold compounds (sodiumaurothiomalate and gold particles < 1.5 microm) did not produce any sign of toxic reactions. A time-dependent increased toxicity in pulmonary cell lines was found for the composite components HEMA and TEGDMA, but not for mercury and gold compounds.

Animals↗
PubMed2000

Thiol-reactive metal compounds inhibit NF-kappa B activation by blocking I kappa B kinase.

Gold compounds are used in the treatment of rheumatoid arthritis. NF-kappa B is a transcription factor implicated in the expression of many inflammatory genes. NF-kappa B is activated by signal-induced phosphorylation and subsequent degradation of inhibitory I kappa B (inhibitory protein that dissociates from NF-kappa B) proteins, and a multisubunit I kappa B kinase (IKK) has been identified previously. We tested the effect of various gold compounds on the activation of NF-kappa B and IKK in LPS-stimulated RAW 264.7 mouse macrophages. A lipophilic gold compound, auranofin, suppressed the LPS-induced increase of nuclear kappa B-binding activity, degradation of I kappa B proteins, and IKK activation. Auranofin also blocked IKK activation induced by TNF and PMA/ionomycin, suggesting that the target of auranofin action is common among these diverse signal pathways. In vitro IKK activity was suppressed by addition of hydrophilic gold compounds, such as aurothiomalate, aurothioglucose, and AuCl3. Other thiol-reactive metal ions such as zinc and copper also inhibited IKK activity in vitro, and induction of IKK in LPS-stimulated macrophages. In vitro IKK activity required the presence of reducing agent and was blocked by addition of thiol group-reactive agents. Two catalytic subunits of IKK complex, IKK alpha and IKK beta, were both inhibited by these thiol-modifying agents, suggesting the presence of a cysteine sulfhydryl group in these subunits, which is critical for enzyme activity. The antiinflammatory activity of gold compounds in the treatment of rheumatoid arthritis may depend on modification of this thiol group by gold.

Animals↗
PubMed1995

[A case of interstitial pneumonia in polymyositis difficult to distinguish from gold pneumonitis].

Rheumatoid arthritis was diagnosed in a 48-year-old woman. She received a gold compound, and 4 weeks after the start of that therapy, interstitial pneumonia appeared. Findings from a muscle biopsy, and high serum CPK and LDH levels indicated that she suffered from polymyositis rather than rheumatoid arthritis. The result of a drug lymphocyte stimulation test (DLST) for the gold compound was more than 200%. Because the usefulness of the DLST for the gold compound in the diagnosis of gold pneumonitis is not thoroughly established, the DLST was also done in patients with rheumatoid arthritis who were receiving the gold compound without side effects, and in normal subjects. Many of the rheumatoid arthritis patients and some of the normal subjects had a positive response to the gold compound. Therefore a positive response on the DLST for the gold compound does not always support the diagnosis of gold pneumonitis.

Antirheumatic Agents↗
PubMed1999

Anti-rheumatic compound aurothioglucose inhibits tumor necrosis factor-alpha-induced HIV-1 replication in latently infected OM10.1 and Ach2 cells.

NF-kappaB is a potent cellular activator of HIV-1 gene expression. Down-regulation of NF-kappaB activation is known to inhibit HIV replication from the latently infected cells. Gold compounds have been effectively used for many decades in the treatment of rheumatoid arthritis. We previously reported that gold compounds, especially aurothioglucose (AuTG) containing monovalent gold ion, inhibited the DNA-binding of NF-kappaB in vitro. In this report we have examined the efficacy of the gold compound AuTG as an inhibitor of HIV replication in latently infected OM10.1 and Ach2 cells. Tumor necrosis factor (TNF)-alpha-induced HIV-1 replication in OM10.1 or Ach2 cells was significantly inhibited by non-cytotoxic doses of AuTG (>10 microM in OM10.1 cells and >25 F.M in Ach2 cells), while 25 microM of the counter-anion thioglucose (TG) or gold compound containing divalent gold ion, HAuCl3, had no effect. The effect of AuTG on NF-kappaB-dependent gene expression was confirmed by a transient CAT assay. Specific staining as well as electron microscopic examinations revealed the accumulation of metal gold in the cells, supporting our previous hypothesis that gold ions could block NF-kappaB-DNA binding by a redox mechanism. These observations indicate that the monovalent gold compound AuTG is a potentially useful drug for the treatment of patients infected with HIV.

Anti-HIV Agents↗
PubMed1983

Auranofin versus injectable gold. Comparison of pharmacokinetic properties.

The new oral gold compound auranofin differs pharmacokinetically from the existing injectable gold compounds such as gold sodium thiomalate. Following a standard 50 mg intramuscular injection of gold sodium thiomalate, plasma gold levels rise sharply, peak between 400 and 800 micrograms/dl in approximately two hours, then decline to approximately 300 micrograms/dl by seven days. With repeated 50 mg weekly injections, stable plasma concentrations are gradually achieved, although absolute levels vary greatly among individual subjects. On the other hand, auranofin is associated with lower (50 to 70 micrograms/dl) and more predictable plasma concentrations. Single-dose kinetic studies using isotopically labelled gold show that the plasma disappearance half-time for gold sodium thiomalate is relatively rapid (approximately six days) compared with 17 days for auranofin. Both compounds are retained within the body over prolonged periods. Retention of auranofin is much less, about 1 percent of the original tracer dose remaining at 180 days, compared with more than 30 percent retention of gold sodium thiomalate. Excretory pathways are notable different. The majority of gold sodium thiomalate (greater than 70 percent) is excreted by the kidneys, with the remaining fraction appearing erratically in the stool. In contrast, the enteric pathway represents the major excretory route for auranofin, with nearly 85 percent of the dose eventually recoverable in the stool and less than 15 percent in the urine. In human subjects, parenterally administered gold is almost universally dispersed among body tissues, although highest concentrations occur in the organs of the reticuloendothelial system and the adrenal and renal cortices. Comparable studies are not available for auranofin, but animal studies show comparatively less affinity for liver, kidney, and spleen. To date, attempts to correlate the pharmacokinetics of the injectable gold compounds with clinical response and toxicity have been largely unsuccessful. The distinctive pharmacokinetic profile of auranofin, when compared with gold sodium thiomalate, may nonetheless account in part for the clinical and pharmacologic differences between these compounds.

Animals↗
PubMed2004

Mitochondrial thioredoxin reductase inhibition by gold(I) compounds and concurrent stimulation of permeability transition and release of cytochrome c.

The effects of auranofin, chloro(triethylphosphine)gold(I) (TEPAu), and aurothiomalate on mitochondrial respiration, pyridine nucleotide redox state, membrane permeability properties, and redox enzymes activities were compared. The three gold(I) derivatives, in the submicromolar range, were extremely potent inhibitors of thioredoxin reductase and stimulators of the mitochondrial membrane permeability transition (MPT). Auranofin appeared as the most effective one. In the micromolar range, it inhibited respiratory chain and glutathione peroxidase activity only slightly if not at all. TEPAu and aurothiomalate exhibited effects similar to auranofin, although TEPAu showed a moderate inhibition on respiration. Aurothiomalate inhibited glutathione peroxidase at concentrations where auranofin and TEPAu were without effect. Under nonswelling conditions, the presence of auranofin and aurothiomalate did not alter the redox properties of the mitochondrial pyridine nucleotides indicating that membrane permeability transition occurred independently of the preliminary oxidation of pyridine nucleotides. Under the same experimental conditions, TEPAu showed a moderate stimulation of pyridine nucleotides oxidation. Mitochondrial total thiol groups, in the presence of the gold(I) derivatives, slightly decreased, indicating the occurrence of an oxidative trend. Concomitantly with MPT, gold(I) compounds determined the release of cytochrome c that, however, occurred also in the presence of cyclosporin A and, partially, of EGTA, indicating its independence of MPT. It is concluded that the specific inhibition of thioredoxin reductase by gold(I) compounds may be the determinant of MPT and the release of cytochrome c.

Animals↗