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PubMed1999

Neurological and electrophysiological examinations on three groups of workers with different levels of exposure to mercury vapors.

The authors performed neurological, visual evoked potentials (VEP) and electroneurography (ENG) examinations on three groups of workers with occupational exposure to mercury vapors (Hg(0)), and on a control group. The exposure of dental professionals (n = 36) was mild, that of chloralkali plant workers (n = 36) was intermediate, and that of workers from mercury works (n = 77) was very high. Symptoms and signs of micromercurialism were observed only in the group with the highest exposure to Hg(0). In comparison with the control group, a shortening of VEP latency and a decrease in amplitude were found in the exposed groups. The VEP changes correlated with Hg(0) excreted in urine after administration of a chelating agent - sodium 2,3-dimercapto-1-propan sulfonate (DMPS). The frequency of abnormal VEP results increased with increasing levels of exposure. ENG changes were observed only in the group with the highest exposure to Hg(0). An isolated decrease of sural nerve conduction velocity was observed in 18% of total workers. In 70% of the cases, this was associated with an abnormality in VEP. The combination of a decrease in sural nerve conduction velocity and an abnormality of VEP seems to be a characteristic pattern of electrophysiological changes in persons exposed to mercury vapors.

Adult↗
PubMed1994

Effects of redox reagents and arsenical compounds on [3H]-cytisine binding to immunoisolated nicotinic acetylcholine receptors from chick brain containing alpha 4 beta 2 subunits.

All known nicotinic receptor alpha subunits include a conserved disulfide bond that is essential for function and is a site for labeling via biochemical modification. In an effort to develop a universal ligand for all subtypes of nicotinic receptors, we previously studied the effects of arsenylation with two compounds, p-aminophenyldichloroarsine (APA) and bromoacetyl-p-aminophenylarsenoxide (BAPA) on nicotinic receptors from Torpedo electroplax. Here we apply these reagents to immunoisolated receptors containing alpha 4, beta 2, and possibly other subunits from chick brain that bind [3H]cytisine with high affinity (KD approximately 5 nM). These are distinct from another receptor subtype that also binds [3H]cytisine and [3H]nicotine and can be arsenylated with APA, but instead contains alpha 5, beta 2, and probably other subunits. Reduction of alpha 4 beta 2 receptors with dithiothreitol blocked [3H]cytisine binding and this effect was reversed upon reoxidation by dithiobisnitrobenzoic acid. APA or BAPA prevented the dithiobisnitrobenzoic acid reactivation of dithiothreitol-treated receptors with IC50 values of 15 and 70 nM, respectively. However, the antiarsenical dimercaptopropanesulfonic acid restored function to APA- or BAPA- "arsenylated" receptors (EC50 approximately 100 microM). APA-treated receptors remained blocked for up to 24 h, but treatment with dimercaptopropanesulfonic acid at any time restored [3H]cytisine binding. APA treatment of reduced receptors protected against irreversible alkylation by bromoacetylcholine, indicating that arsenylation occurs at least in part in the agonist binding site. Thus, these reagents have similar effects on different nicotinic receptor subtypes from both muscle and nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed2002

Fanconi's syndrome, acute renal failure, and tonsil ulcerations after colloidal bismuth subcitrate intoxication.

A 22-year-old woman ingested 5.4 g of colloidal bismuth subcitrate (CBS) in a suicide attempt. After ingestion, she presented with Fanconi's syndrome and acute renal failure to our unit. On the third day after ingestion, she was anuric. Ulcerations of both tonsils were observed 8 days after intoxication. Sodium-2,3-dimercapto-1-propanesulfonate (DMPS) is shown to be an effective chelating agent of heavy metal intoxications, but it has only a small effect on elimination of bismuth salts in patients with renal insufficiency without hemodialysis. In our case, we initiated hemodialysis and intravenous treatment with DMPS 60 hours after intoxication. By repeated measurements of bismuth concentrations in serum and dialyzed fluid, we showed its successful elimination. Serum bismuth level decreased from 640 microg/L to 15 microg/L within 6 days. With elimination of bismuth, renal function improved, and tonsil ulcerations healed. Hemodialysis was discontinued on day 14. Follow-up examination 6 weeks later showed normal renal function. Clinicians should be aware that acute renal failure and tonsil ulcerations can occur after CBS intoxication. Generally, acute renal failure caused by CBS intoxication is reversible. Treatment with the chelating agent DMPS in combination with hemodialysis is highly effective in reducing the serum bismuth level in patients with acute renal failure.

Acute Kidney Injury↗
PubMed1998

[Lead poisoning caused by a Greek ceramic cup].

HISTORY AND ADMISSION FINDINGS: A 24-year-old woman, an administrative employee, was admitted with colicky abdominal pain and constipation, as well as breathing-related chest pain of recent onset with cough and sometimes blood-streaked sputum. She had previously been unsuccessfully treated for gastritis and adnexitis. On physical examination revealed diffuse, ill-defined abdominal pain on pressure and mild tachycardia, but was otherwise unremarkable. INVESTIGATIONS: Electrocardiogram, chest radiogram, lung scintigraphy, abdominal sonography, oesophago-gastro-duodenoscopy and gynaecological examination indicated nothing abnormal. Laboratory tests showed microcytic anemia, slight leucocytosis and anisocytosis, as well as polychromasia and basophilic stippling of erythrocytes. The 24-h urinary porphyrin concentration was elevated. DIAGNOSIS TREATMENT AND COURSE: Precise differentiation of porphyrins in urine, stool and erythrocytes by enzymatic measurement first raised the suspicion of lead poisoning. Whole-blood lead concentration was markedly raised to 600 micrograms/l (normal up to 90 micrograms/l) and 170 micrograms/dl in urine (normal up to 80 micrograms/dl). A ceramic cup from Greece was traced as the source of the lead, the patients having regularly for over 2 1/2 months drunk lemon instant-tea from it. She was treated with oral doses of DMPS (sodium salt of 2,3-dimercapto-1-propanesulphonic acid), 5-10 mg/kg 3x daily for 2 days, followed by 2.5 mg/kg 2 x daily, until lead concentrations in blood and urine had become normal, when all symptoms disappeared: detoxification was complete within 4 months. CONCLUSION: This case impressively illustrates how difficult it can be to diagnose lead poisoning and identify its source. Oral DMPS is a practicable and efficacious form of treatment.

Abdominal Pain↗
PubMed2002

Small heat-shock proteins regulate membrane lipid polymorphism.

Thermal stress in living cells produces multiple changes that ultimately affect membrane structure and function. We report that two members of the family of small heat-shock proteins (sHsp) (alpha-crystallin and Synechocystis HSP17) have stabilizing effects on model membranes formed of synthetic and cyanobacterial lipids. In anionic membranes of dimyristoylphosphatidylglycerol and dimyristoylphosphatidylserine, both HSP17 and alpha-crystallin strongly stabilize the liquid-crystalline state. Evidence from infrared spectroscopy indicates that lipid/sHsp interactions are mediated by the polar headgroup region and that the proteins strongly affect the hydrophobic core. In membranes composed of the nonbilayer lipid dielaidoylphosphatidylethanolamine, both HSP17 and alpha-crystallin inhibit the formation of inverted hexagonal structure and stabilize the bilayer liquid-crystalline state, suggesting that sHsps can modulate membrane lipid polymorphism. In membranes composed of monogalactosyldiacylglycerol and phosphatidylglycerol (both enriched with unsaturated fatty acids) isolated from Synechocystis thylakoids, HSP17 and alpha-crystallin increase the molecular order in the fluid-like state. The data show that the nature of sHsp/membrane interactions depends on the lipid composition and extent of lipid unsaturation, and that sHsps can regulate membrane fluidity. We infer from these results that the association between sHsps and membranes may constitute a general mechanism that preserves membrane integrity during thermal fluctuations.

Feedback↗
PubMed2002

Critical points in charged membranes containing cholesterol.

Epifluorescence microscopy is used to determine phase diagrams for lipid monolayers containing binary mixtures of cholesterol or dihydrocholesterol and dimyristoylphosphatidylserine, as well as ternary mixtures that also contain ganglioside G(M1). The phase diagrams are unusual in that they show multiple critical points: two upper miscibility critical points and one lower miscibility critical point. These critical points all are associated with the formation of condensed complexes between these lipids and cholesterol (or dihydrocholesterol). The miscibility critical pressures depend on subphase pH and ionic strength. Changes in critical pressures due to changes in subphase composition are closely related to changes in membrane electrostatic pressure and surface ionization.

Animals↗
PubMed2000

Condensed complexes, rafts, and the chemical activity of cholesterol in membranes.

Epifluorescence microscopy studies of mixtures of phospholipids and cholesterol at the air-water interface often exhibit coexisting liquid phases. The properties of these liquids point to the formation of "condensed complexes" between cholesterol and certain phospholipids, such as sphingomyelin. It is found that monolayers that form complexes can incorporate a low concentration of a ganglioside G(M1). This glycolipid is visualized by using a fluorescently labeled B subunit of cholera toxin. Three coexisting liquid phases are found by using this probe together with a fluorescent phospholipid probe. The three liquid phases are identified as a phospholipid-rich phase, a cholesterol-rich phase, and a condensed complex-rich phase. The cholera toxin B labeled ganglioside G(M1) is found exclusively in the condensed complex-rich phase. Condensed complexes are likely present in animal cell membranes, where they should facilitate the formation of specialized domains such as rafts. Condensed complexes also have a major effect in determining the chemical activity of cholesterol. It is suggested that this chemical activity plays an essential role in the regulation of cholesterol biosynthesis. Gradients in the chemical activity of cholesterol should likewise govern the rates and direction of intracellular intermembrane cholesterol transport.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1989

Mechanism of mercury(II) reductase and influence of ligation on the reduction of mercury(II) by a water soluble 1,5-dihydroflavin.

The nature and rate of reduction of Hg2+ to Hg0 by 1,5-dihydro-3,(3-sulfopropyl)lumiflavin (FIH2) in buffered aqueous solutions (pH 4.7) is dependent on the ligation of Hg2+. In the presence of N,N-bis(2-hydroxyethyl)glycine or when ligated to ethylenediaminetetraacetic acid, the reduction is first order in Hg2+ and FIH2. The apparent second-order rate constant with N,N-bis(2-hydroxyethyl)glycine (2.2 x 10(6) M-1.s-1) is much greater than that in the presence of ligating ethylenediaminetetraacetic acid (1.5 x 10(2) M-1.s-1). When ligated by mercaptoethanesulfonate, reduction of Hg2+ by FIH2 is characterized by a pronounced lag phase, which is dependent on the concentration of mercaptoethanesulfonate. The rate decreases with increase in mercaptoethanesulfonate, and with an excess of 10 equivalents, Hg2+ is not reduced by FIH2. These observations show that bis-ligation by thiolate greatly decreases the reducibility of Hg2+ and that further ligation by thiolate further retards the reaction. Comparison of oxidation-reduction potentials at various pH values shows that bis-ligation (or greater) of Hg2+ by thiolate substantially lowers the reduction potential of Hg2+ below that of 3(3-sulfopropyl)lumiflavin (FIox). Thus, the ease of reduction of Hg2+ complexes by FIH2 decreases with increasing thermodynamic stability of the complex. These results do not support the proposed role of the thiol functionalities in facilitating the mercury(II) reductase (Hg:NADP+ oxidoreductase, EC 1.16.1.1)-catalyzed reduction of Hg2+ through tris- or tetraligation of Hg2+.

Edetic Acid↗
PubMed2000

Electric field effect on cholesterol-phospholipid complexes.

Monolayer mixtures of dihydrocholesterol and phospholipids at the air-water interface are used to model membranes containing cholesterol and phospholipids. Specific, stoichiometric interactions between cholesterol and some but not all phospholipids have been proposed to lead to the formation of condensed complexes. It is reported here that an externally applied electric field of the appropriate sign can destabilize these complexes, resulting in their dissociation. This is demonstrated through the application of an electric field gradient that leads to phase separations in otherwise homogeneous monolayers. This is observed only when the monolayer composition is close to the stoichiometry of the complex. The electric field effect is analyzed with the same mean field thermodynamic model as that used previously to account for pairs of upper miscibility critical points in these mixtures. The concentrations of dihydrocholesterol, phospholipid, and complex vary strongly and sometimes discontinuously in the monolayer membrane in the field gradient. The model is an approximation to a two-dimensional liquid in which molecules freely exchange between free and complexed form so that the chemical potentials are constant throughout the membrane. The calculations are illustrated for a complex of about 15 molecules, composed of 5 cholesterol molecules and 10 phospholipid molecules.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

Contributions to maxima in protein kinase C activation.

In many lipid systems, the activity of protein kinase C (PKC) exhibits a peak followed by a decline as the mol % of one component is increased. In these systems, an increase in one lipid component is always at the expense of another or accompanied by a change in total lipid concentration. Here we report that in saturated phosphatidylserine (PS)/phosphatidylcholine (PC)/diacylglycerol (DAG) mixtures, increasing PS or DAG at the expense of PC revealed an optimal mol % PS, dependent on mol % DAG, with higher mol % PS diminishing activity. The decrease at high mol % PS is probably not attributable simply to more gel-phase lipid due to the higher melting temperature of saturated PS versus PC because a similar peak in activity occurred in unsaturated lipid systems. Increasing the total lipid concentration at suboptimal mol % PS provided the same activity as higher mol % PS at lower total lipid concentration. However, at optimal mol % PS, activity increased and then decreased as a function of total lipid concentration. PKC autophosphorylation also exhibited an optimum as a function of mol % PS, and increasing the PKC concentration increased the mol % PS at which activity decreased, both for autophosphorylation and for heterologous phosphorylation. Formation of two-dimensional crystals of PKC on lipid monolayers also exhibited a peak as a function of mol % PS, and the unit cell size of the crystals formed shifts from 50 x 50 A at low mol % PS to 75 x 75 A at higher PS. Collectively, these data suggest the existence of optimal lipid compositions for PKC activation, with increased quantity of these domains serving to dilute out enzyme-substrate aggregates and/or enzyme-enzyme aggregates on the lipid surface.

Amino Acid Sequence↗
PubMed2004

Conformational regulation of alpha 4 beta 1-integrin affinity by reducing agents. "Inside-out" signaling is independent of and additive to reduction-regulated integrin activation.

The alpha(4)beta(1)-integrin (very late antigen-4 (VLA-4), CD49d/CD29) is an adhesion receptor involved in the interaction of lymphocytes, dendritic cells, and stem cells with the extracellular matrix and endothelial cells. This and other integrins have the ability to regulate their affinity for ligands through a process termed "inside-out" signaling that affects cell adhesion avidity. Several mechanisms are known to regulate integrin affinity and conformation: conformational changes induced by separation of the C-terminal tails, divalent ions, and reducing agents. Recently, we described a fluorescent LDV-containing small molecule that was used to monitor VLA-4 affinity changes in live cells (Chigaev, A., Blenc, A. M., Braaten, J. V., Kumaraswamy, N., Kepley, C. L., Andrews, R. P., Oliver, J. M., Edwards, B. S., Prossnitz, E. R., Larson, R. S., and Sklar, L. A. (2001) J. Biol. Chem. 276, 48670-48678). Using the same molecule, we also developed a fluorescence resonance energy transfer-based assay to probe the "switchblade-like" opening of VLA-4 upon activation. Here, we investigated the effect of reducing agents on the affinity and conformational state of the VLA-4 integrin simultaneously with cell activation initiated by inside-out signaling through G protein-coupled receptors or Mn(2+) in live cells in real time. We found that reducing agents (dithiothreitol and 2,3-dimercapto-1-propanesulfonic acid) induced multiple states of high affinity of VLA-4, where the affinity change was accompanied by an extension of the integrin molecule. Bacitracin, an inhibitor of the reductive function of the plasma membrane, diminished the effect of dithiothreitol, but had no effect on inside-out signaling. Based on this result and differences in the kinetics of integrin activation, we conclude that conformational activation of VLA-4 by inside-out signaling is independent of and additive to reduction-regulated integrin activation.

Anti-Bacterial Agents↗
PubMed1996

Comparative evaluation of chelating agents on the mobilization of cadmium: a mechanistic approach.

A comparative evaluation of chelating agents, namely, diethyl dithiocarbamate (DDC), dimethyl dithiocarbamate (DMDC), 1,4,8,11-tetraazacyclotetradecane (CYCLAM), 1,4,8,12-tetraazacyclopentadecane (TACPD), 2,3-dimercaptosuccinic acid (DMSA), and 2,3-dimercapto-1-propane sulfonate (DMPS) was conducted to assess their efficacy against acute cadmium (Cd) toxicity. DMSA and DMPS appeared to be most effective in reducing mortality as well as Cd burden of liver, kidneys, and brain in cadmium intoxicated mice. DMDC reduced Cd levels only in liver and kidneys, while DDC significantly enhanced its level in brain. CYCLAM and TACPD significantly increased the Cd level in liver and kidneys and were ineffective in brain. The therapeutic index as well as therapeutic efficacy was highest for DMSA followed by DMPS and DMDC. A fair degree of correlation was found to exist between (1) stability constant of Cd chelates and percent survival (r = .438, (2) stability constant and percent transport (r = .479), and (3) percent survival and percent transport (r =.447). However, the lipophilicity did not show any appreciable correlation with percent survival and stability constant of Cd chelates.

Animals↗
PubMed1998

Heavy metals and fertility.

Heavy metals have been identified as factors affecting human fertility. This study was designed to investigate whether the urinary heavy metal excretion is associated with different factors of infertility. The urinary heavy metal excretion was determined in 501 infertile women after oral administration of the chelating agent 2,3-dimercaptopropane-1-sulfonic acid (DMPS). Furthermore, the influence of trace element and vitamin administration on metal excretion was investigated. Significant correlations were found between different heavy metals and clinical parameters (age, body mass index, nationality) as well as gynecological conditions (uterine fibroids, miscarriages, hormonal disorders). Diagnosis and reduction of an increased heavy metal body load improved the spontaneous conception chances of infertile women. The DMPS test was a useful and complementary diagnostic method. Adequate treatment provides successful alternatives to conventional hormonal therapy.

Adult↗
PubMed1995

Combined chelation treatment for polonium after simulated wound contamination in rat.

Contaminated puncture wounds were simulated in rat by intramuscular injection of 210Po. The aim of the study was to determine the effectiveness of chelation treatment as a function of time, dosage, and route of chelate administration. Ten newly synthesized substances containing vicinal sulphydryl and carbodithioate groups were used and their effect was compared with that of chelators clinically applicable in man--BAL (2,3-dimercaptopropane-1-ol), DMPS (2,3-dimercaptopropane-1-sulphonate), DMSA (meso-2,3-dimercaptosuccinic acid), and DDTC (sodium diethylamine-N-carbodithioate). The results indicate first that complete removal of 210Po from the injection site is achieved by only two local injections of DMPS, beginning as late as 2 h after injection of 210Po. Second, many of the substances used merely induce translocation of 210Po from the injection site into other tissues. Third, a combined local treatment at the injection site with DMPS plus repeated systemic, subcutaneous, treatments with HOEtTTC (N,N'-di-(2-hydroxyethyl)ethylenediamine-N,N-biscarbodithioate), a derivative of DDTC, results after 2 weeks in a reduction of the estimated total body retention of 210Po to about one-third of that in untreated controls. In the latter case the cumulative excretion of 210Po increased from 8 to 54%, mainly via the faeces.

Animals↗
PubMed1979

Note on the metabolism of the mercury chelating agent sodium 2,3-dimercaptopropane-1-sulfonate.

Chromatographic analysis of the radioactive urine obtained after injection into rats of [1,3-(14)C] dimercaptopropane sodium sulfonate (DMPS, Dimaval) showed that part of the administered chelating agent is excreted unchanged. This was confirmed by the results of studies of sulfur excretion in the different fractions of the urine as well as by titration of the excreted thiol groups. The results show that, at least in rats, DMPS is not involved in important metabolic reactions.

Animals↗
PubMed2006

Neither DMPS nor DMSA is effective in quantitative elimination of elemental mercury after intentional IV injection.

BACKGROUND: Intravenous injection of elemental mercury (Hg) is rare and considered relatively harmless. Treatment recommendations vary and the effectiveness of chelation therapy is controversial. CASE REPORT: A 27-year-old man intravenously injected 1.5 mL of elemental Hg. Within 12 hours he became febrile, tachycardic and dyspneic. Physical examination was unremarkable. X-rays showed scattered radiodense deposits in the lung, heart, intestinal wall, liver and kidney. The serum Hg level on admission was 172 microg/L and peaked on day 6 at 274 microg/L. Cumulative renal elimination during a five day oral treatment period with 2,3-dimercaptopropane-1-sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) was 8 mg and 3 mg, respectively. CONCLUSION: Although urinary excretion could be enhanced during chelation therapy, Hg deposits in organs resulted in negligible elimination of mercury compared to the exposed dose.

Adult↗
PubMed2000

Urinary excretion of trace elements in humans after sodium 2,3-dimercaptopropane-1-sulfonate challenge test.

OBJECTIVE: To evaluate the effects of intravenous sodium 2,3-dimercaptopropane-1-sulfonate (DMPS, Dimaval) on urinary excretion of essential trace elements in subjects who received this chelating agent as a mercury challenge test. SUBJECTS: Eleven subjects sought medical attention due to concern with the toxicity of mercury released from dental amalgam fillings. DESIGN: The subjects were given DMPS 3 mg/kg intravenously. Spot urine samples were collected 1 hour before and 1 hour after the DMPS dose for laboratory analysis. In addition to mercury, the urinary excretion of copper, zinc, selenium, magnesium, manganese, molybdenum, chromium, cobalt, and aluminum were measured. RESULTS: A significant increase in urinary excretion of mercury (3- to 107-fold) was observed after the DMPS dose. The DMPS treatment led to a 2- to 119-fold increase in copper excretion; 3- to 43.8-fold in selenium excretion; 1.6- to 44-fold in zinc excretion; and 1.75- to 42.7-fold in magnesium excretion. The excretion of manganese, chromium, cobalt, aluminium, and molybdenum remained unchanged. CONCLUSIONS: In this study, an intravenous DMPS challenge test produced a significant increase in mercury excretion and also led to an increased excretion of copper, selenium, zinc, and magnesium.

Chelating Agents↗