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PubMed1985

[The effect of an organic gold compound on porphyrin metabolism, with reference to interaction with lead].

Inhibition of the activity of delta-aminolevulinic acid dehydratase by heavy metals such as Cu, Cd and Au has been thought to be related to the inhibition of heme bio-synthesis in the bone marrow. This study investigates the interaction between lead and gold on porphyrin metabolism. Gold thiomalate (Au-T) was injected subcutaneously 10 times into the backs of rabbits in doses of 1, 10 and 100 mg per capita for 30 days. The latter two groups of animals showed mild anemia, but they showed neither reticulocytosis nor increase of free erythrocyte protoporphyrin (FEP). In rabbits administered lead only or lead plus gold thiomalate, however, reticulocytosis and an increase in FEP levels were observed. Therefore, the etiology of anemia may be different between rabbits administered gold thiomalate and rabbits administered lead. Rabbits injected with Au-T showed an increase in urinary coproporphyrin (CP-U) excretion. The maximum concentration of CP-U in the gold groups was about 3 times as high as that in the control group, but the increment was lower than that in the lead group. Rabbits injected with Au-T showed a higher concentration of gold in the kidneys than in other tissues. In those injected lead and Au-T together, concentration of gold in all tissues was higher than in those administered Au-T only. Proteinuria was observed in the rabbits injected Au-T. The increase in CP-U in the gold-injected rabbits was assumed to be related to the increase in gold concentration in the kidneys.

Animals↗
PubMedDate not supplied

Effects of gold compounds on the function of phagocytic cells. I. Suppression of phagocytosis and the generation of chemiluminescence by polymorphonuclear leukocytes.

The effect of sodium aurothiomalate (GSTM) and auranofin (AF) on polymorphonuclear (PMN) leukocytes has been assessed using a Candida albicans phagocytosis method and by the generation of chemiluminescence of activated cells. Both compounds inhibited the phagocytosis of Candida albicans but at therapeutic concentrations this was only consistent and significant with AF. This drug, but not GSTM, also had a suppressive effect on the generation of chemiluminescence. These results suggest that AF has a more potent effect on PMN function than GSTM. They also suggest that the effect of these compounds in vitro may differ from each other and from the effects previously reported with other phagocytic cells, notably peripheral blood mononuclear cells.

Candida albicans↗
PubMed1991

[The effect of an oral gold compound, auranofin, on bronchial responsiveness to inhaled methacholine in well-controlled bronchial asthma].

Recently, in Japan, auranofin (6 mg/day) has been demonstrated to be a useful treatment for patients with moderate to severe asthma in a double-blind clinical trial. Therefore, to investigate the mechanism of auranofin on bronchial asthma, we examined pulmonary functions and bronchial responsiveness to inhaled methacholine in well-controlled asthmatics after 12 wks of treatment with auranofin, in a double-blind, placebo-controlled fashion. Twenty-five adult patients with asthma received orally 3 mg of auranofin or inactive placebo twice daily for 12 weeks. Bronchial responsiveness, pulmonary function tests and concentrations of gold in the blood were measured before and 6 and 12 wks after the therapy. Bronchial responsiveness (PD35-Grs) was significantly decreased after 12 wks of treatment with auranofin, compared with that 12 wks after treatment with inactive placebo. We suggest that inhibition of bronchial hyperresponsiveness by auranofin is one of the mechanisms by which auranofin is effective against bronchial asthma.

Adult↗
PubMed1989

Covalent binding to alpha-macroglobulins of a protein with free SH groups produced by activated B cells: blocking by D-penicillamine and gold compounds.

alpha 2-Macroglobulin (alpha 2M) complexed with proteinases or modified by the action of amines has been shown to affect immune responses in vitro, though as yet the mechanisms are poorly understood. Supernates from rabbit lymphoid cells cultured in medium with normal rabbit serum and 35S-methionine (or 14C-leucine) were found to contain intensely radiolabeled alpha-macroglobulins (alpha M) (alpha 1 and alpha 2) on electrophoresis. When human alpha 2 M, instead of rabbit serum, was added to cultures, it also appeared radiolabeled, suggesting that lymphocyte-produced proteins (LyP) formed complexes with serum alpha M. These alpha M-associated LyP were produced in greater quantity when lymphocytes were cultured in the presence of mitogens; they were not produced by cells cultured in the presence of cycloheximide; they were produced primarily by B cells rather than T cells or macrophages. Pretreatment of serum or alpha M with methylamine, enhanced rather than inhibited the formation of LyP-alpha M complexes, a finding which is contrary to that expected if the LyP were a proteinase. Since this methylamine treatment of alpha M also results in the generation of free SH groups from the internal thioester bonds of alpha M, the formation of disulfide bonds between LyP and alpha M was considered. Indeed, (a) the LyP-alpha M complex formation was inhibited by N-ethylmaleimide, aurothiomalate, sodium aurothioglucose or D-penicillamine; (b) blocking the SH groups with NEM, of either culture fluid supernates or serum, had an inhibitory effect on the formation of these complexes; (c) the LyP-alpha M complexes were dissociated by sodium dodecyl sulfate (SDS) only after their reduction with 2-mercaptoethanol (2-ME). Thus, a disulfide bond was formed between alpha M and LyP with free SH groups (SH-LyP). Molecular sieving by high performance liquid chromatography (HPLC) of the serum-free radiolabeled supernates indicated that SH-LyP eluted at a position corresponding to a polypeptide of mol. wt of about 22,000. However, SDS-PAGE of the 22,000 mol. wt HPLC fraction showed that the major protein was approximately mol. wt 11,000 under both reducing and non-reducing conditions. In addition, the SH-LyP reduced by 2-ME from its binding site on alpha 2M had a mol. wt of about 11,000 in SDS-PAGE, suggesting that it was a non-covalent homodimer of mol. wt 11,000 polypeptides. We suggest that alpha 2M as well as SH-LyP may affect the immune system by functioning as SH-reactive agents.

Animals↗
PubMed2000

Antioxidant enzymes; possible mechanism of gold compound treatment in rheumatoid arthritis.

Reactive oxygen species play a critical role in inflammatory processes including rheumatoid disorders. Antioxidant therapy strategies have been postulated for the treatment of rheumatoid diseases. In this study, we investigated activities and therapeutic implications of antioxidant enzymes in rheumatoid disorders. Activities of antioxidant enzymes glutathione peroxidase, glutathione reductase and catalase were examined in the blood of rheumatic patients and healthy controls. Activity of catalase was decreased significantly, while activities of glutathione peroxidase and glutathione reductase remained unchanged. Thioredoxin reductase is an antioxidant enzyme having an important regulatory task of thiol redox status and intracellular signaling processes coupled with the glutathione system. We also observed that in liver mitochondrial calf thioredoxin reductase was inhibited by antirheumatic drug goldthioglucose in the manner similar to intracellular thioredoxin reductase. Furthermore, during the treatment by goldthioglucose, gold is accumulated in lysosomes of macrophages. Our results suggest that although antioxidant enzyme activities were down-regulated in rheumatoid patients, we can decrease ROS generation by macrophages via inhibition thioredoxin reductase by goldthioglucose.

Journal Article↗
PubMed2004

Effects of antirheumatic gold compounds on the conversion of xanthine dehydrogenase to oxidase in rabbit liver cytosol in vitro.

Effects of auranofin (AUR), aurothioglucose (AuTG) and aurothiomalate (AuTM) on the conversion of xanthine dehydrogenase (XD) to oxidase (XO) in the cytosolic fraction from rabbit liver were examined. AUR had no effect on the conversion of XD to XO at concentrations up to 50 microM, whereas at concentrations ranging from 10 to 25 microM, AuTG and AuTM induced the conversion of XD to XO. The constituents of AuTG and AuTM, aurous ion (Au+), but not mercaptosuccinic acid and 1-thio-beta-D-glucose, converted XD to XO in a similar degree to AuTG and AuTM. This means that Au (I) moiety has an important role in the AuTG- and AuTM-induced conversion of XD to XO. Furthermore, N-acetyl-L-cysteine (NAC) and British anti-Lewisite (BAL) reconverted AuTG and AuTM-induced XO to XD, implying that clinical activity of NAC and BAL against toxic reactions of AuTG and AuTM is partially due to the XO reconversion. These results suggest that AuTG and AuTM have the potential to convert XD to its reactive oxygen species-generating form, XO, and that this effect may be correlated with cytotoxic actions of these drugs.

Animals↗
PubMed2006

Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4.

Toll-like receptors (TLRs), which are activated by invading microorganisms or endogenous molecules, evoke immune and inflammatory responses. TLR activation is closely linked to the development of many chronic inflammatory diseases including rheumatoid arthritis. Auranofin, an Au(I) compound, is a well-known and long-used anti-rheumatic drug. However, the mechanism as to how auranofin relieves the symptom of rheumatoid arthritis has not been fully clarified. Our results demonstrated that auranofin suppressed TLR4-mediated activation of transcription factors, NF-kappaB and IRF3, and expression of COX-2, a pro-inflammatory enzyme. This suppression was well correlated with the inhibitory effect of auranofin on the homodimerization of TLR4 induced by an agonist. Furthermore, auranofin inhibited NF-kappaB activation induced by MyD88-dependent downstream signaling components of TLR4, MyD88, IKKbeta, and p65. IRF3 activation induced by MyD88-independent signaling components, TRIF and TBK1, was also downregulated by auranofin. Our results first demonstrate that auranofin suppresses the multiple steps in TLR4 signaling, especially the homodimerization of TLR4. The results suggest that the suppression of TLR4 activity by auranofin may be the molecular mechanism through which auranofin exerts anti-rheumatic activity.

Animals↗
PubMed1994

Effect of an oral gold compound, auranofin, on non-specific bronchial hyperresponsiveness in mild asthma.

BACKGROUND: A recent double blind clinical trial in Japan has shown that auranofin (6 mg/day) is a useful treatment for patients with moderate to severe asthma. To investigate the mechanism of action of auranofin the bronchial responsiveness to inhaled methacholine has been studied in well controlled asthmatic subjects. METHODS: Nineteen adult asymptomatic asthmatic subjects received auranofin (3 mg orally twice a day) or inactive placebo in random order for 12 weeks in a double blind fashion. Bronchial responsiveness to inhaled methacholine and pulmonary function tests were measured at the same time on different days before, and six and 12 weeks after, each treatment. RESULTS: Non-specific bronchial hyperresponsiveness 12 weeks after treatment with auranofin was decreased compared with that before treatment with auranofin and 12 weeks after treatment with inactive placebo, although the treatment did not improve pulmonary function tests. CONCLUSIONS: Non-specific bronchial hyperresponsiveness 12 weeks after treatment with auranofin is decreased in a group of mild asymptomatic asthmatic patients with normal lung function.

Adult↗
PubMed1989

Selective inhibition of endothelium-dependent relaxation by gold-containing compounds.

Gold-containing compounds inhibited endothelium-dependent relaxation mediated by acetylcholine and the calcium ionophore A23187 in isolated rabbit thoracic aortic rings. Auranofin was the most potent gold-containing compound studied, producing approximately 40% inhibition of vascular relaxation at a concentration of 1 microM. Concentration-response curves to vascular relaxation produced by sodium nitroprusside were significantly shifted 5-fold to the left in the presence of auranofin. However, concentration-response curves to vascular relaxation produced by nitric oxide or isoproterenol were unaffected by auranofin. A series of other gold-containing compounds also inhibited endothelium-dependent relaxation with varying degrees of potency, but none approaching that observed with auranofin. These findings reveal that certain gold-containing compounds are potent and selective inhibitors of endothelium-dependent relaxation.

Animals↗