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PubMed1999

Different effects of two gold compounds on muscle contraction, membrane potential and ryanodine receptor.

Effects of gold sodium thiomalate and NaAuCl4 on skeletal muscle function were studied using intact single fibres of frog skeletal muscle and fragmented sarcoplasmic reticulum prepared from frog and rabbit skeletal muscles. Gold sodium thiomalate at a concentration of 500 microM decreased tension amplitude by 27% and resting membrane potential by 5.3% after 30 and 22 min, respectively. The duration of tetanus tension was markedly shortened by 500 microM gold sodium thiomalate. When 10 microM NaAuCl4 was applied to gold sodium thiomalate-pretreated fibres, the fibres lost the ability to contract upon electrical stimulation, similar to the effects of 10 microM NaAuCl4 alone. In the presence of thiomalic acid, on the other hand, NaAuCl4 did not completely block tetanus tension even at 50 microM. Thiomalic acid also inhibited NaAuCl4-induced membrane depolarization. These findings suggest that thiomalate masks the effects of gold ion on muscle function. When sarcoplasmic reticulum vesicles were incorporated into lipid bilayers, exposure of the cis side of the Ca2+-release channel to 100 microM gold sodium thiomalate rapidly increased the open probability of the channel 3.3-fold, from 0.032 in controls to 0.105, with an increase in number of open events and a decrease in mean closed time. The ability of NaAuCl4 to activate the Ca2+-release channel was much stronger than that of gold sodium thiomalate. Only 1 microM NaAuCl4 was enough to activate the channel and this gold was effective from either side of the channel. These results suggest that gold sodium thiomalate could be used as an antirheumatic drug without considering severe side-effects on skeletal muscle. Coexistent thiomalate probably contributes to protection of muscle function from side-effects of gold ion.

Action Potentials↗
PubMed1987

Gold compounds alter distribution of protein kinase C activity in human neutrophils.

Slow translocation of protein kinase C was observed by both auranofin and gold sodium thiomalate pretreatment of neutrophils. Both gold compounds failed to influence the activity of this enzyme directly when cell-free studies were performed. In intact neutrophils incubated with 5.1-20.3 microM auranofin, protein kinase C activity decreased in the cytosol in a time- and dose-dependent manner. Concomitantly, the levels of the membrane-associated protein kinase C were significantly elevated, although the amount of activity recovered could not account for that lost from the cytosol. Gold sodium thiomalate (5.0 microM-0.505 mM) demonstrated similar effects but with lesser potency than auranofin. In confirmation of previous results, phorbol myristate acetate (PMA), a cellular stimulus, also induced the translocation of protein kinase C. Key differences were that the reaction was rapid (occurring within minutes after PMA addition) and that relative recovery of kinase activity from the particulate fraction was fourfold greater. The relationship between gold compound-mediated kinase C redistribution and inhibition of neutrophil responses remains to be elucidated.

Cell Membrane↗
PubMed1979

Inhibitory effects of a new oral gold compound on HeLa cells.

Auranofin (AF), a recently introduced oral antirheumatic coordinated gold compound, was investigated for its antitumor potential. Due to certain similarities with the antitumor-coordinated compound, cis-Diamminedichloroplatinum II, we studied the effects of AF on cell proliferation. These studies included assessing DNA, RNA, and protein synthesis as measured by incorporation of 3H-thymidine, 3H-uridine, and 3H-leucine, respectively, into HeLa cells. AF was shown to exert a dose-dependent inhibition on DNA synthesis and to inhibit 3H-thymidine uptake more rapidly and persistently than 3H-uridine or 3H-leucine uptake at a gold concentration of 75--100 micrograms/dl. These three parameters were inhibited with a 24-hour exposure to 100 micrograms/dl. The inhibition of 3H-thymidine uptake in HeLa pretreated for 6 hours with 50 or 100 micrograms/dl of gold was found to be irreversible. No change in tracer uptake was observed in the acid-soluble pool or in the uptake of 3H-2-deoxy-D-glucose in these cells. Furthermore, HeLa cells demonstrated marked reductions in viability and oxygen uptake after exposure to AF. Dose-dependent surface morphological changes, e.g., blebbing, pitting, were noted in these cells after a brief treatment period. These results suggest this coordinated gold compount exerts a significant inhibitory effect on essential biological processes and functions.

Aurothioglucose↗
PubMed1988

Carcinogenicity study of auranofin, an orally administered gold compound, in mice.

Auranofin, a gold-containing compound, was administered to Charles River CD-1 mice for 18 months to assess its possible carcinogenicity. The mice were dosed orally with 1.0, 3.0, or 6.0 (increased to 9.0 on Day 294) mg/kg/day. Each dose group and each of two control groups contained 110 males and 110 females. Survival was greater than 70% at the end of the study. No effect of the treatment on neoplastic or nonneoplastic lesions was found. This is in contrast to the results reported in rats. Auranofin in rats produced a heavy metal nephropathy characterized by acute coagulative necrosis, subacute renal cortical fibrosis, chronic cytomegaly and karyomegaly, and finally renal cortical neoplasia (adenomas and adenocarcinomas). The lack of effect of auranofin on tumor incidence in mice suggests the findings in rats may be species specific.

Administration, Oral↗
PubMed1989

Inhibition of hydrolytic enzymes by gold compounds. I. beta-Glucuronidase and acid phosphatase by sodium tetrachloroaurate (III) and potassium tetrabromoaurate (III).

Purified bovine liver beta-glucuronidase (beta-D-glucuronide glucuronohydrolase, EC 3.2.1.32) and wheat germ acid phosphatase (orthophosphoric monoesterphosphohydrolase, EC 3.1.3.2) were inhibited with freshly dissolved and 24 h aquated tetrahaloaurate (III) compounds. Rate and equilibrium inhibition constants were measured. From this data two acid phosphatases species were observed. Equilibrium inhibition constants ranged from 1 to 12.5 microM for the various gold compounds toward both enzymes. The first order rate constants ranged between 0.005 and 0.04 min.-1 for most reactions with the exception of the fast reacting acid phosphatase which had values as high as 2.6 and 2.8 min.-1. It is observed that the beta-glucuronidase is rapidly inhibited during the equilibrium phase before the more slower reaction covalent bond formation takes place. The acid phosphatases form the covalent bonds more rapidly, especially the faster reacting species suggesting a unique difference in the active site geometry to that of the more slowly reacting species. The tightly bonded gold (III)-enzyme complex is probably the reason for its toxicity and non-anti-inflammatory use as a drug.

Acid Phosphatase↗
PubMed1988

Effect of two gold compounds on lysosomes.

The effect of two gold(I) compounds on stability of lysosomes in vitro was studied. Lysosomes from homogenates of rat kidney cortex were isolated by differential centrifugation. These lysosomes were incubated at 37 degrees C with widely varied concentrations of sodium aurothiomalate and sodium aurothiosulphate for 5, 35, and 65 minutes. Acid phosphatase activities were measured and used as an indication of lysosomal membrane stability in the presence and absence of drugs. The enhanced release of acid phosphatase from lysosomes by aurothiomalate and aurothiosulphate was related to dose, but the drugs differed substantially in their potencies. The disruptive effect on lysosomes was more marked for aurothiosulphate than for aurothiomalate. In addition, both drugs inhibited acid phosphatase activities at relatively high gold concentrations. Aurothiomalate had a moderate and aurothiosulphate a weaker inhibitory effect on the enzyme. Our results indicate that aurothiomalate and aurothiosulphate exert their beneficial effect in the treatment of rheumatoid arthritis through mechanism(s) other than lysosomal membrane stabilisation.

Acid Phosphatase↗
PubMed1998

Human placenta thioredoxin reductase. Isolation of the selenoenzyme, steady state kinetics, and inhibition by therapeutic gold compounds.

Human thioredoxin reductase is a pyridine nucleotide-disulfide oxidoreductase closely related to glutathione reductase but differing from the latter in having a Cys-SeCys (selenocysteine) sequence as an additional redox center. Because selenoproteins cannot be expressed yet in heterologous systems, we optimized the purification of the protein from placenta with respect to final yield (1-2 mg from one placenta), specific activity (42 units/mg), and selenium content (0.94 +/- 0.03 mol/mol subunit). The steady state kinetics showed that the enzyme operates by a ping-pong mechanism; the value of kcat was 3330 +/- 882 min-1, and the Km values were 18 microM for NADPH and 25 microM for Escherichia coli thioredoxin. The activation energy of the reaction was found to be 53.2 kJ/mol, which allows comparisons of the steady state data with previous pre-steady state measurements. In its physiological, NADPH-reduced form, the enzyme is strongly inhibited by organic gold compounds that are widely used in the treatment of rheumatoid arthritis; for auranofin, the Ki was 4 nM when measured in the presence of 50 microM thioredoxin. At 1000-fold higher concentrations, that is at micromolar levels, the drugs also inhibited human glutathione reductase and the selenoenzyme glutathione peroxidase.

Antirheumatic Agents↗
PubMed1986

Regulation of metallothionein gene expression in mammalian cells by gold compounds.

Metallothioneins are a class of low molecular weight, cysteine-rich proteins. Metallothioneins bind heavy metals and are thought to play a role in metal metabolism. Auranofin, an antiarthritic gold compound, is a potent inducer of metallothionein in Chinese hamster ovary cells. The induction of metallothionein by auranofin was mediated by active transcription of the gene and new mRNA was accumulated within 30 min after the exposure of Chinese hamster ovary cells to the drug. The extent of metallothionein induction was related to the concentration of the compound and was affected by the nature of the ligand attached to the gold molecule. A subline of these Chinese hamster ovary cells was established by growing them in the presence of normally cytotoxic concentrations of auranofin. In this auranofin-resistant cell line, the metallothionein genes were actively transcribed in the presence of auranofin, suggesting a relationship between cytotoxic action of auranofin and metallothionein gene transcription. Regulation of metallothionein gene transcription may play an important role in the molecular mechanism(s) of action auranofin and resistance to it.

Animals↗
PubMed1999

In vitro lymphocyte reactivity to gold compounds in the diagnosis of contact hypersensitivity.

The use of the lymphocyte transformation test (LTT) in the diagnosis of contact hypersensitivity to gold was studied in 8 patients who had positive patch tests to gold salts, and in 8 control subjects who were negative to such patch tests. Gold sodium thiosulfate and gold chloride were added to cultures of lymphocytes, which were labeled by 3H-thymidine after 96 h. The lymphocyte stimulation index was calculated as the beta-counts in stimulated cultures divided by those in control cultures. The index was statistically significantly higher for the patient group (p=0.005-0.04) than for the control group. Levels of interferon-gamma (IFN-gamma) were determined for the supernatants of the lymphocyte cultures. An index IFN-gamma, which is defined as the level of IFN-gamma in stimulated cultures divided by that in control cultures, was statistically significantly higher for the patient group (p=0.01-0.006). The LTT stimulation index showed specificity and sensitivity between 67 and 80%, the respective values for Index IFN-gamma being between 73 and 100% when the patch test was used as a reference method. Evaluation of lymphocyte reactivity might be of future interest in the diagnosis of allergic reactions to gold if the sensitivity and specificity can be improved.

Adult↗
PubMed1988

The oral gold compound auranofin triggers arachidonate release and cyclooxygenase metabolism in the alveolar macrophage.

We examined the effect of in vitro incubation with the oral gold compound auranofin (AF) on arachidonic acid (AA) release and metabolism by rat alveolar macrophages (AMs). AF stimulated dose- and time-dependent release of 14C-AA from prelabeled AMs, which reached 4.7 +/- 0.3% (mean +/- SEM) of incorporated radioactivity at 10 micrograms/ml for 90 min, as compared to 0.5 +/- 0.1% release following control incubation for 90 min (p less than 0.001). Similar dose- and time-dependent synthesis of thromboxane (Tx) A2 (measured as TxB2) and prostaglandin (PG) E2 was demonstrated by radioimmunoassay of medium from unlabeled cultures, reaching 18-fold and 9-fold, respectively, of the control values at 10 micrograms/ml AF for 90 min (p less than 0.001 for both). AF-induced TxB2 and PGE2 synthesis was inhibited by indomethacin as well as by pretreatment with methylprednisolone. No increase in the synthesis of immunoreactive leukotrienes (LT) B4 or C4 was noted at any dose or time of AF. High performance liquid chromatographic separation of 14C-eicosanoids synthesized by prelabeled AMs confirmed that AF induced the release of free AA and its metabolism to cyclooxygenase, but not 5-lipoxygenase, metabolites. The ability of AF to trigger macrophage AA metabolism may be relevant to the exacerbation of certain inflammatory processes which sometimes accompany gold therapy.

Animals↗
PubMed1982

Use of a gold compound for the treatment of pemphigus foliaceus in a foal.

A 4-month-old foal was examined because of generalized exfoliative dermatitis, with thick scales, extensive crusting, and oozing of serum. A diagnosis of pemphigus foliaceus was made by histologic and immunopathologic examinations of skin biopsy specimens. The foal was treated with a gold compound, aurothioglucose (1 mg/kg once weekly for 14 weeks). For the initial 5 weeks, high-dose glucocorticoid treatments also was used. The skin disorder resolved entirely after 12 weeks of treatment.

Animals↗
PubMed1994

Paradoxical derepression of collagenase gene expression by the antirheumatic gold compound aurothiomalate.

The neutral metalloproteinase collagenase is known to be, among others, one of the key enzymes promoting joint destruction in patients with rheumatoid arthritis. Because inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-alpha, are considered to activate collagenase gene expression through activation of the transcription factor activator protein-1, we examined whether the water-soluble gold compound aurothiomalate (AuTM) influenced collagenase gene expression, using phorbol ester-treated human fibroblasts. However, AuTM did not prevent phorbol ester-mediated activation of activator protein-1 DNA-binding activity and subsequent induction of collagenase gene expression. In contrast, AuTM counteracted the repressive effects of glucocorticoids on collagenase gene expression and restored collagenase mRNA levels. The molecular target of this paradoxical AuTM action was suggested to be the glucocorticoid receptor.

Adult↗
PubMed2001

Inhibition of interleukin-12 production by auranofin, an anti-rheumatic gold compound, deviates CD4(+) T cells from the Th1 to the Th2 pathway.

1. Interleukin-12 (IL-12) may play a central role in the development and progression of rheumatoid arthritis by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated the effect of auranofin (AF), an anti-rheumatic gold compound, on IL-12 production in mouse macrophages and dendritic cells, and studied whether AF-mediated inhibition of IL-12 production could regulate a cytokine profile of antigen (Ag)-primed CD4(+) Th cells. 2. Treatment with AF significantly inhibited IL-12 production in lipopolysaccharide (LPS)-stimulated macrophages and also in CD40L-stimulated dendritic cells. AF-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. AF did not influence the cell surface expression of the class II MHC molecule and the costimulatory molecules CD80 and CD86. 3. Addition of recombinant IL-12 to cultures of AF-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in Ag-primed CD4(+) T cells. 4. The in vivo administration of AF resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with LPS or heat-killed Listeria monocytogenes (HKL), leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in Ag-primed CD4(+) T cells. 5. These findings may explain some known effects of AF including anti-rheumatic effects and the inhibition of encephalitogenicity, and point to a possible therapeutic use of AF in the Th1-mediated immune diseases such as autoimmune diseases.

Animals↗
PubMed2001

Induction of cellular antioxidative stress genes through heterodimeric transcription factor Nrf2/small Maf by antirheumatic gold(I) compounds.

Gold(I)-containing compounds have long been used in the treatment of rheumatoid arthritis (RA), but the molecular mechanism of their action has remained largely unknown. In this paper we have demonstrated that gold(I) drugs selectively activate the DNA binding of a heterodimer consisting of the basic-leucine zipper transcription factors Nrf2 and small Maf. Once bound to its recognition DNA sequence termed antioxidant-responsive element or Maf-recognition element, Nrf2/small Maf induces a set of antioxidative stress genes, including heme oxygenase-1 and gamma-glutamylcysteine synthetase, whose products have been demonstrated to contribute to the scavenging of reactive oxygen species and to exhibit anti-inflammatory effects. Our findings suggest that stimulation of antioxidative stress response through activation of Nrf2/small Maf may be a pharmacologically important part of the actions of gold(I) drugs for the treatment of rheumatoid arthritis. Alternatively, activation of Nrf2/small Maf may be a protective response of cells against toxic effects of the drugs.

Antirheumatic Agents↗
PubMedDate not supplied

Methyl ester of N-formylmethionyl-leucyl-phenylalanine: chemotactic responses of human blood monocytes and inhibition of gold compounds.

N-formylmethionyl-leucyl-phenylalanine, a potent hemotactic peptide for human polymorphonuclear leukocytes, is less chemotactic for human blood monocytes. Esterification of the N-formylated tripeptide enhances its chemotactic activity for monocytes by more than 4 logs, whereas a decrease by 3 logs is observed for polymorphonuclear leukocytes. These results indicate the participation of the C-terminal carboxyl group in chemotaxis of different cell types. We have also observed the selective inhibition of chemotactic responsiveness of human blood monocytes by a clinically useful antirheumatic drug, sodium aurothiomalate. Since this is the first in vitro cell migration model of inflammation in which gold compounds have demonstrated activity in micromolar concentrations, it suggests a site of action for this antirheumatic drug.

Chemotaxis, Leukocyte↗
PubMed1986

Effects of gold compounds on function of phagocytic cells. Comparative inhibition of activated polymorphonuclear leukocytes and monocytes from rheumatoid arthritis and control subjects.

The effect of sodium aurothiomalate and auranofin on the generation of superoxide anions (O2-) by polymorphonuclear leukocytes (PMNLs) and adherent mononuclear phagocytic cells (AMNCs) has been investigated. Sodium aurothiomalate at final concentrations of 1, 10, and 100 micrograms Au/ml and auranofin ranging from 0.1 to 2.0 micrograms Au/ml were used in the reactions involving all cell types. Results have been compared between cells drawn from normal controls and patients with active rheumatoid disease. The effect of gold compounds on both cell types was assessed following activation by phorbol myristate acetate (1 X 10(-8) M) and N-formyl-methionyl-leucyl-phenylalanine (1 X 10(-4) M) using a cytochrome c reduction method. Sodium aurothiomalate at the maximum concentration modestly inhibited O2- generation by PMNLs but not AMNCs. Auranofin inhibits O2- generation by both cell types. Inhibition of cells from patients with rheumatoid arthritis was greater than that seen with cells from normal controls.

Arthritis, Rheumatoid↗
PubMed1986

Effects of gold compounds on leukotriene B4, leukotriene C4 and prostaglandin E2 production by polymorphonuclear leukocytes.

The effects of auranofin (AF) and sodium aurothiomalate (GSTM) on the production of specific arachidonic acid metabolites by chemotactic tripeptide activated polymorphonuclear leukocytes has been investigated using radioimmunoassay techniques. AF insignificantly enhanced the production of leukotrienes B4 and C4 at a concentration of 0.5 microgram Au/ml. However, at increasing concentrations, this drug suppressed the production of these metabolites in a dose dependent manner. In contrast, GSTM did not affect the production of either leukotriene at the concentrations tested. Of particular interest, prostaglandin E2 production was not affected by either gold compound. Both leukotrienes and prostaglandins are metabolized from arachidonic acid and are potent mediators of inflammation. The inhibition of leukotriene production may be another mechanism by which AF manifests its antiinflammatory effects in patients with rheumatoid arthritis.

Adult↗