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PubMed1986

Fluorometric determination of 2,3-dimercaptopropane-1-sulfonic acid and other dithiols by precolumn derivatization with bromobimane and column liquid chromatography.

The increasing therapeutic use of dithiol metal binding agents, such as 2,3-dimercaptopropane-1-sulfonic acid (DMPS), has stimulated the need for a sensitive and selective method for their determination in biological fluids. A method has now been developed in which DMPS was converted to a highly fluorescent and stable derivative by reaction with bromobimane in aqueous solution at pH 8.3. The reaction was complete within 5 min. The derivative was separated by ion-pair reversed-phase column liquid chromatography. The mass spectrum of the derivative showed that two bromobimane molecules reacted with one DMPS molecule. This method is also applicable to the determination of other dithiols. The detection limit for DMPS in urine is 10 pmol per 20-microliters injection and the precision is 7.4% at the 100-pmol level. The fluorescence response was linear from 1 to 400 micron. This method was used to determine DMPS in the urine of rabbits treated with this metal binding agent. In addition, total DMPS was determined by adding sodium tetrahydridoborate to the same urine to reduce biotransformed and oxidized DMPS.

Animals↗
PubMed1998

On-column formation of arsenic-glutathione species detected by size-exclusion chromatography in conjunction with arsenic-specific detectors.

The 'retention analysis method', which is based on size-exclusion chromatography (SEC) in conjunction with an arsenic-specific detector (graphite furnace atomic absorption spectrometer, GFAAS), was used to study the effect of pH (range 2.0-10.0), temperature (4, 25 and 37 degrees C), and the concentration of glutathione in the mobile phase (0.5-7.5 mM) on the formation of arsenic-glutathione species after injection of sodium arsenite using phosphate-buffered saline solutions as mobile phases. The formation of arsenic-GSH species was facilitated by low temperatures (4 degrees C), pH 6.0-8.0 and high concentrations of glutathione (7.5 mM) in the mobile phase. Simulating the physicochemical parameters found inside human red blood cells (approximately 3.0 mM glutathione, 37 degrees C, pH 7.4) and hepatocytes (approximately 7.5 mM glutathione, 37 degrees C, pH 7.4), SEC-GFAAS provided evidence for the formation of arsenic-glutathione species under these conditions. In addition, the 'chelating agent', sodium DL-2,3-dimercapto- -propanesulfonate (1.0 and 2.0 mM) was demonstrated to bind arsenous acid stronger in the presence of glutathione (7.5 mM) under these conditions (PBS buffer, pH 7.4, 37 degrees C).

Arsenic↗
PubMed2004

The outer pore of the glutamate receptor channel has 2-fold rotational symmetry.

The ligand binding domain of glutamate receptors (GluRs) has 2-fold rotational symmetry. The structure including the symmetry of the GluR ion channel remains undefined. Here we used substituted cysteines in the pore-lining M3 segment of the AMPAR GluR-A subunit and various cysteine-reactive agents to study the structure of the channel during gating. We find that cysteines substituted at A+6, located in the highly conserved SYTANLAAF motif, are grouped in pairs consistent with a 2-fold symmetry in the extracellular part of the pore. To account for this symmetry and crosslinking, we propose that the M3 segments in two neighboring GluR subunits are kinked within SYTANLAAF in opposite directions relative to the central axis of the pore. Our results extend the 2-fold rotational symmetry from the ligand binding domain to at minimum the extracellular part of the channel and suggest a model of gating movements in GluR pore-forming domains.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

Conformation of phosphatidylserine in bilayers as studied by Fourier transform infrared spectroscopy.

The 13C labeled lipid 1[1'-13C]DPPS-NH4+ and its metal salts were used to unambiguously assign all carbonyl vibrations in the infrared spectrum of phosphatidylserines. It is shown that the C=O stretching band at 1741 cm-1 of phosphatidylserines previously assigned to the sn-1 C = O vibration contains contributions from both the sn-1 and the sn-2 carbonyls. The C=O stretching band at frequencies between 1715 and 1730 cm-1 previously assigned to the sn-2 C=O vibration also contains contributions from both carbonyl groups. The frequency dependence observed with the ester carbonyls primarily reflects hydrogen bonding and the polarity of the immediate vicinity. Conformational changes are accounted for in terms of frequency shifts if the conformational change involves the disposition of the C=O groups and in turn the hydrogen bonding properties. The infrared spectra of phospholipids dispersed in aqueous medium in the liquid crystalline state are inconsistent with a simple phospholipid conformation, e.g., with a conformation as found in the single-crystal structure of 1,2-dimyristoyl-sn-phosphatidylcholine and 1,2-dilauroyl-rac-phosphatidylethanolamine. The spectra support the hypothesis proposed earlier (Hauser et al., Biochemistry, 1988) on the basis of existing single-crystal phospholipid structures and NMR evidence. The hypothesis states that several conformations are present in liquid crystalline phospholipid dispersions.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbon Isotopes↗
PubMed2003

Redox control of platelet aggregation.

Sulfhydryl and disulfide metabolism in platelet function has recently reemerged as a focus of platelet research. In this study we tested the effect of redox buffer on platelet aggregation and the effect of reduced glutathione (GSH) and platelet activation on sulfhydryl exposure in the platelet fibrinogen receptor, alpha IIb beta 3. In the presence of subthreshold concentrations of agonist, physiologic concentrations of GSH (10 microM) stimulated platelet aggregation and secretion. These effects were found with more than one platelet agonist and with different low molecular weight thiols, including homocysteine. The effect of low molecular weight thiols was reproduced with the peptide LSARLAF which directly activates platelets through alpha IIb beta 3, suggesting that the mechanism is at the level of this integrin. After determining optimal sulfhydryl labeling conditions for alpha IIb beta 3 (5 mM EDTA, 37 degrees C, 60 min), we found that GSH (10 microM) generated sulfhydryls in the beta 3 subunit. To determine if the requirement was for reducing equivalents or for a redox potential (ratio of GSH to GSSG), aggregation was further studied with the addition of low concentrations of GSSG to the GSH. With a ratio of GSH/GSSG of 5/1, similar to that of blood, the addition of GSSG potentiated the stimulatory effect as compared to GSH alone. This indicates that, for potentiation of aggregation, GSH is not simply reducing disulfide bonds; there is rather a requirement for a certain redox potential. Additional studies performed in the absence of added glutathione showed an increase in sulfhydryl labeling in the beta 3 subunit during platelet activation. Finally, we show that vicinal dithiols of platelet surface proteins are involved in the sulfhydryl-dependent pathways of platelet activation. In summary, these data imply that the redox potential of blood regulates activation of the alpha IIb beta 3 integrin and together with other reports in the literature suggest that disulfide bond cleavage with sulfhydryl generation in beta 3 is involved in activation of this receptor.

Arsenicals↗
PubMed1997

Activation of protein kinase C by coexisting diacylglycerol-enriched and diacylglycerol-poor lipid domains.

To test the hypothesis that activation of protein kinase C (PKC) is related to the interface between coexisting diacylglycerol- (DAG-) enriched and DAG-poor phases, the thermotropic phase behavior of the ternary mixtures dimyristoylphosphatidylcholine (DMPC)/dimyristoylphosphatidylserine (DMPS)/dioleoylglycerol (DO), DMPC/DMPS/1-palmitoyl-2-oleoylglycerol (PO), and DMPC/DMPS/dimyristoylglycerol (DM) was analyzed and compared with the ability of the lipid mixtures to support PKC activity. Differential scanning calorimetry (DSC) was used to monitor the gel-to-liquid crystalline phase transition as a function of the mole fraction of DO (chiDO), PO (chiPO), or DM (chiDM) in DMPC/DMPS (1:1) multilamellar vesicles (MLVs) and of chiDO in large unilamellar vesicles (LUVs). The addition of DAG at low mole fractions gave rise to the appearance of two or more overlapping transitions. The phase boundaries of the ternary mixtures deduced from the partial phase diagrams were chiDO = approximately 0.10 and approximately 0.3 for DMPC/DMPS/DO, chiPO = approximately 0.05 and approximately 0.4 for DMPC/DMPS/PO, and chiDM = approximately 0.025 and approximately 0.5-0.6 for DMPC/ DMPS/DM. Above these mole fractions of DAG, the transitions again became very sharp. The ability of the lipid mixtures to support activity of PKC alpha and PKC eta was examined below and above the gel-to-liquid crystalline phase transition. In the gel phase, PKC activity went through a maximum as a function of increasing mole fraction of each DAG and was restricted to lipid compositions in which coexisting phases were observed. Maximal activity decreased with increasing saturation of the DAG. In the fluid state, maximal PKC activity was shifted to higher DO mole fractions and the peak was much broader. Collectively, these data support a role for both the presence and nature of interface between compositionally distinct domains in activation of PKC.

Calorimetry, Differential Scanning↗
PubMedDate not supplied

Efficacy of combined chelation in lead intoxication.

The combination of a bone lead mobilizer, viz., CaNa2EDTA, and a soft tissue depleter such as meso-2,3-dimercaptosuccinic acid (DMSA) or the sodium salt of 2,3-dimercapto-1-propane-sulfonic acid (DMPS) was investigated for its efficacy to enhance the excretion of lead, to reduce its body burden, and to reverse certain lead-induced biochemical alterations by either of them alone in rats. The administration of CaNa2EDTA or DMSA was more effective than that of DMPS, and the combination of CaNa2EDTA and DMSA was more efficient than that of CaNa2EDTA and DMPS or the individual chelators in enhancing urinary/fecal excretion of lead, in reducing hepatic, renal, and femur concentration of lead, and in restoring lead-induced inhibition of blood delta-aminolevulinic acid dehydratase and increase in blood zinc protoporphyrin and urinary delta-aminolevulinic acid levels. The brain lead was depleted by DMSA only, but the combined chelation failed to improve upon the ability of DMSA. However, chelation therapy increased diuresis and tissue depletion of zinc.

Animals↗
PubMed2002

Determination of arsenic metabolic complex excreted in human urine after administration of sodium 2,3-dimercapto-1-propane sulfonate.

Sodium 2,3-dimercapto-1-propane sulfonate (DMPS) has been used to treat acute arsenic poisoning. Presumably DMPS functions by chelating some arsenic species to increase the excretion of arsenic from the body. However, the excreted complex of DMPS with arsenic has not been detected. Here we describe a DMPS complex with monomethylarsonous acid (MMA(III)), a key trivalent arsenic in the arsenic methylation process, and show the presence of the DMPS-MMA(III) complex in human urine after the administration of DMPS. The DMPS-MMA(III) complex was characterized using electrospray tandem mass spectrometry and determined by using HPLC separation with hydride generation atomic fluorescence detection (HGAFD). The DMPS-MMA(III) complex did not form a volatile hydride with borohydride treatment. On-line digestion with 0.1 M sodium hydroxide following HPLC separation decomposed the DMPS-MMA(III) complex and allowed for the subsequent quantification by hydride generation atomic fluorescence. Arsenite (As(III)), arsenate (As(V)), monomethylarsonic acid (MMA(V)), dimethylarsinic acid (DMA(V)), MMA(III), and DMPS-MMA(III) complex were analyzed in urine samples from human subjects collected after the ingestion of 300 mg of DMPS. The administration of DMPS resulted in a decrease of the DMA(V) concentration and an increase of the MMA(V) concentration excreted in the urine, confirming the previous results. The finding of the DMPS-MMA(III) complex in human urine after DMPS treatment provides an explanation for the inhibition of arsenic methylation by DMPS. Because MMA(III) is the substrate for the biomethylation of arsenic from MMA(V) to DMA(V), the formation of DMPS-MMA(III) complex would reduce the availability of MMA(III) for the subsequent biomethylation.

Arsenic↗
PubMed2004

Mercury binding to the chelation therapy agents DMSA and DMPS and the rational design of custom chelators for mercury.

Clinical chelation therapy of mercury poisoning generally uses one or both of two drugs--meso-dimercaptosuccinic acid (DMSA) and dimercaptopropanesulfonic acid (DMPS), commercially sold as Chemet and Dimaval, respectively. We have used a combination of mercury L(III)-edge X-ray absorption spectroscopy and density functional theory calculations to investigate the chemistry of interaction of mercuric ions with each of these chelation therapy drugs. We show that neither DMSA nor DMPS forms a true chelate complex with mercuric ions and that these drugs should be considered suboptimal for their clinical task of binding mercuric ions. We discuss the design criteria for a mercuric specific chelator molecule or "custom chelator", which might form the basis for an improved clinical treatment.

Chelating Agents↗
PubMed2000

Significance of gaseous NO for ammonia oxidation by Nitrosomonas eutropha.

Nitrification by the obligately lithoautotrophic ammonia oxidizer Nitrosomonas eutropha was significantly inhibited when nitric oxide was removed from the culture medium by means of intensive aeration and turbulence. Nearly complete recovery of ammonia oxidation could be achieved by adding 100 ppm NO to the supplied air. Inhibition of ammonia oxidation occurred also upon addition of the NO binding agent 2,3-Dimercapto-1-propane-sulfonic acid (DMPS). Recovery of ammonia oxidation occurred within 3 h in the presence of 100 ppm NO and within 76 h in the absence of externally added NO. In co-cultures of N. eutropha and the NO detoxifying bacterium Pseudomonas PS88, hardly any nitrification was detectable and release of NO was extremely low when the heterotroph was provided with an organic substrate. When cells of Pseudomonas PS88 were added to a mixotrophically nitrifying culture of N. eutropha the release of NO decreased drastically upon the addition and ammonia oxidation ceased. These results confirm for the first time the significance of NO in the course of ammonia oxidation by N. eutropha.

Ammonia↗
PubMed2001

Effect of dithiol chelating agents on [3H]MK-801 and [3H]glutamate binding to synaptic plasma membranes.

2,3-Dimercaptopropanol (BAL- British Anti-Lewesite) is a dithiol chelating agent used for the treatment of heavy metal poisoning, however, BAL can produce neurotoxic effects in a variety of situations. Based on the low therapeutic efficiency of BAL other dithiols were developed and DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercaptopropane-1-sulfonic acid) are becoming used for treatments of humans exposed to heavy metals. In the present investigation the effect of dithiols in the glutamatergic system was examined. The results showed that BAL inhibited [3H]MK-801 and [3H]glutamate binding in a concentration-dependent manner. At 100 microM BAL and DMSA caused a significantly inhibition of [3H]MK-801 binding to brain membranes (p < 0.05 by Duncan's multiple range test). BAL at 100 microM caused an inhibition of 40% on [3H]glutamate binding. DMPS and DMSA had no significant effect on [3H]glutamate binding. Dithiotreitol (DTT), abolished the inhibitory effect of BAL on [3H]MK-801 binding. The protection exerted by DTT suggests that BAL inhibit [3H]MK-801 binding by interacting with cysteinyl residues that are important for redox modulation of receptor responses. ZnCl2 inhibited [3H]glutamate and [3H]MK-801 binding to brain synaptic membrane; nevertheless, the inhibitory effect was slight more accentuated for [3H]MK-801 than [3H]glutamate binding (p < 0.05). The inhibition caused by 10 microM ZnCl2 on [3H]MK-801 binding was attenuated by BAL. The findings present in this study may provide the evidence that BAL affect the glutamatergic system and these effects can contributed to explain, at least in part, why BAL, in contrast to DMPS and DMSA is neurotoxic.

Animals↗
PubMed2004

Characterization of phospholipid mixed micelles by translational diffusion.

The concentration dependence of the translational self diffusion rate, D (s), has been measured for a range of micelle and mixed micelle systems. Use of bipolar gradient pulse pairs in the longitudinal eddy current delay experiment minimizes NOE attenuation and is found critical for optimizing sensitivity of the translational diffusion measurement of macromolecules and aggregates. For low volume fractions Phi (Phi\\ le 15% v/v) of the micelles, experimental measurement of the concentration dependence, combined with use of the D (s)= D (o)(1-3.2lambdaPhi) relationship, yields the hydrodynamic volume. For proteins, the hydrodynamic volume, derived from D (s) at infinitely dilute concentration, is found to be about 2.6 times the unhydrated molecular volume. Using the data collected for hen egg white lysozyme as a reference, diffusion data for dihexanoyl phosphatidylcholine (DHPC) micelles indicate approximately 27 molecules per micelle, and a critical micelle concentration of 14 mM. Differences in translational diffusion rates for detergent and long chain phospholipids in mixed micelles are attributed to rapid exchange between free and micelle-bound detergent. This difference permits determination of the free detergent concentration, which, for a high detergent to long chain phospholipid molar ratio, is found to depend strongly on this ratio. The hydrodynamic volume of DHPC/POPC bicelles, loaded with an M2 channel peptide homolog, derived from translational diffusion, predicts a rotational correlation time that slightly exceeds the value obtained from peptide (15)N relaxation data.

Biophysics↗
PubMed2000

Biological mercury measurements before and after administration of a chelator (DMPS) and subjective symptoms allegedly due to amalgam.

The aim of the study was to explore multivariately the relationship between subjective symptoms allegedly due to amalgam and mercury measurements before and after administration of a chelator. Of 120 participants, the mercury concentrations in urine (U-Hg) and plasma (P-Hg) before and after a chelating agent or placebo were determined as were the numbers of fillings and symptoms allegedly due to subjective symptoms. The dental status was charted. Blood was analysed on 13 parameters. The analysis revealed neither the parameters in blood nor the subjective symptoms to be associated with a dimension dominated by 'mercury indicators'. The final analysis was therefore performed with 'number of subjective symptoms' and enabled to distinguish two subsamples. One subsample was characterised by > 2 subjective "symptoms", highest scores for U-Hg, P-Hg and filled surfaces, and chewing gum for > 1 h a day. The other subsample comprised the subjects with few filled surfaces and low U-Hg and P-Hg, but was not characterised by "no subjective symptoms". The chelator was considered neither to invalidate nor to improve these findings and was concluded not to be helpful in diagnosing "symptoms". The chelator caused side effects in 42% of the subjects and the placebo in 27%. A relationship between amalgam fillings and subjective symptoms could not be shown. Therefore, the mere fact of knowing to have amalgam fillings was assumed to be the reason why subjective symptoms were attributed to amalgam and side effects were ascribed to the treatment.

Adult↗
PubMed1985

Prediction of kidney mercury content by isotope techniques.

A 61-year-old female patient accidentally aspirated liquid mercury during a medically ordered diagnostic procedure. To develop animal-based guidelines, liquid mercury was introduced into the lungs of four dogs. Based on the study of these animals, a method of predicting the kidney inorganic mercury burden was developed using radioactive isotope dilution techniques. It was further demonstrated in dogs that oral administration of dimercaptopropane sulfonate (DMPS) increased mercury excretion and reduced the kidney burden. A rat experiment was performed permitting a statistical evaluation of the assumptions basic to the use of the method. The method was applied to the patient with the result that the kidney inorganic mercury burden was predicted to be 28.1 mg, 8 months after the accident. Treatment with DMPS increased urinary excretion and the post-treatment kidney burden was estimated at 19.6 mg Hg. Inasmuch as the radioactive dose to the subject may be kept at a negligible level and because sensitive methods exist for measurement of radioactive and stable mercury concentrations, the technique may be applicable in special cases to the estimation of kidney inorganic mercury burdens incurred by industrial exposure.

Animals↗
PubMed1998

Comparison of enhanced elimination of bismuth in humans after treatment with meso-2,3-dimercaptosuccinic acid and D,L-2,3-dimercaptopropane-1-sulfonic acid.

Two groups of 12 human volunteers, who had been treated with colloidal bismuth subcitrate, because of Helicobacter pylori-associated gastritis, participated in the study. The patients received a single dose of meso-2,3-dimercaptosuccinic acid (DMSA) or D,L-2,3-dimercaptopropane-1-sulfonic acid (DMPS) at a dose of 30 mg kg-1 in a randomized single blind study. In contrast to DMPS, increasing concentrations of bismuth in blood were observed during the first 4 h after intake of DMSA. In urine, both chelators induced a 50-fold increase in urinary bismuth excretion compared with the control urines. The treatment was well tolerated. The results indicate that both DMSA and DMPS effectively increase the elimination of bismuth in human urine. Consequently, both chelators may be of benefit in the treatment of patients with bismuth intoxication.

Adult↗