Lipophilic Chelating Agent Research Articles

Reductions in plasma and urine mercury concentrations following N,N′bis-(2-mercaptoethyl) isophthalamide (NBMI) therapy: a post hoc analysis of data from a randomized human clinical trial

Environmental mercury exposure possesses a significant risk to many human populations. At present there are no effective treatments for acute mercury toxicity. A new compound, N,N′bis-(2-mercaptoethyl) isophthalamide (NBMI), a lipophilic chelating agent was created to tightly/irreversibly bind mercury. A post hoc dose-dependent analysis of NBMI therapy was undertaken on data from a randomized controlled NBMI human treatment trial on 36 Ecuadorian gold miners with elevated urinary mercury concentrations. Study subjects were randomly assigned to receive 100 milligram (mg) NBMI/day, 300 mg NBMI/day, or placebo for 14 days. For each study subject daily mg NBMI dose/Kilogram (Kg) bodyweight were determined and plasma and urine mercury concentrations (micrograms (µg)/Liter (L)) on study day 1 (pre-NBMI treatment), 15 (after 14 days of NBMI treatment) and 45 (30 days after NBMI treatment) were correlated with NBMI dosing using the linear regression statistic in SAS. Regression revealed significant inverse correlations between increasing per mg NBMI/Kg bodyweight/day and reduced concentrations of urinary and plasma mercury on study day 15 (reduced by in urine = 18–20 µg/L and plasma = 2 µg/L) and study day 30 (reduced by in urine = 15–20 µg/L and plasma = 4 µg/L) and significant correlations between reductions in mercury concentrations in urine and plasma. Significant 30% reductions in urinary mercury concentrations per mg NBMI/Kg bodyweight/day administered for 14 days were observed. This study supports the dose-dependent ability of NBMI therapy to significantly reduce mercury concentrations, particularly in the urine, in an acutely mercury exposed human population. NBMI therapy should be evaluated in other mercury exposed populations.

Effects of chelating agents on heavy metals in Hepatitis C Virus (HCV) patients.

Heavy metals are released into the environment through both human and natural sources, may have a direct hepatic toxicity and are involved in chronic liver diseases. Modification in the regulation of heavy metals metabolism enhanced hepatitis c virus (HCV) replication which ultimately reduced outcomes of anti-viral therapy in chronic HCV patients. Chelation therapy with new drugs seems to eradicate HCV and may prevent liver complications. The present study was planned to explore the effects of MiADMSA (lipophilic chelating agent) for achieving maximum heavy metals elimination in hepatitis c virus patients with minimum side effects. For this purpose concentration of heavy metal was determined in HCV patients and established correlation of heavy metals between healthy persons and HCV patients. Atomic absorption spectrophotometer (AAS) was used to explore them. Concentrations of heavy metal in different samples (blood serum, nails and hair) of patients and healthy individuals. Result revealed that heavy metals (Lead, Cobalt, Cadmium, Manganese, Iron and Cooper) concentration were significantly higher in blood of HCV patients as compared to normal persons, but some metals like Ni and Zn were present in normal concentration and in low concentration respectively. After chelation with monoisoamyl DMSA (MiADMSA) a significant amount of heavy metals was excreted in the urine in a dose dependent manner. It was generally observed from the results that TDS is a better treatment option than BD for chelation of heavy metals in hepatitis c virus patients. This chelation therapy will be helpful to reverse the HCV related health problems.

2,6-Dihydroxybenzaldehyde Analogues of the Iron Chelator Salicylaldehyde Isonicotinoyl Hydrazone: Increased Hydrolytic Stability and Cytoprotective Activity against Oxidative Stress.

Salicylaldehyde isonicotinoyl hydrazone (SIH) is a small molecule and lipophilic chelating agent that firmly binds ferric ions from the cellular labile iron pool and is able to protect various tissues against oxidative damage. Previously, SIH possessed the best ratio of cytoprotective efficiency to toxicity among various iron chelators, including the desferrioxamine, deferiprone, and deferasirox used in clinical practice. Here, we prepared a series of 2,6-dihydroxybenzaldehyde aroylhydrazones as SIH analogues with an additional hydroxyl group that can be involved in the chelation of metal ions. Compound JK-31 (2,6-dihydroxybenzaldehyde 4-chlorobenzohydrazone) showed the best cytoprotective efficiency among the studied compounds including SIH. This compound significantly protected H9c2 cardiomyoblast cells against oxidative stress induced by various pro-oxidants, such as hydrogen peroxide, tert-butyl hydroperoxide, paraquat, epinephrine, N-acetyl- p-benzoquinone imine (a toxic metabolite of paracetamol), and 6-hydroxydopamine. The exceptional cytoprotective activity of JK-31 was confirmed using epifluorescence microscopy, where JK-31-treated H9c2 cells maintained a higher mitochondrial inner membrane potential in the presence of a lethal dose of hydrogen peroxide than was observed with cells treated with SIH. Hence, this study demonstrates the deleterious role of free iron ions in oxidative injury and the potential of 2,6-dihydroxybenzaldehyde aroylhydrazones in the prevention of various types of cardiac injuries, highlighting the need for further investigations into these compounds.

Temperature‐induced surfactant‐ mediated pre‐concentration of uranium assisted by complexation

AbstractCloud‐point extraction (CPE) was used with lipophilic chelating agent to extract uranium(VI) from aqueous solutions. The methodology used is based on the formation of metal complexes soluble in a micellar phase of a non‐ionic surfactant, Triton X‐114. The metal ions complexes are then extracted into the surfactant‐rich phase at a temperature above the cloud‐point temperature. The influence of surfactant concentration on extraction efficiency was studied and the advantage of adding 8‐hydroxyquinoline (8HQ) as lipophilic chelating agent was evidenced. High extraction efficiency was observed, indicating the feasibility of extracting U(VI) using CPE. This study describes a four‐step process—(1) extraction, (2) thermo‐induced phase splitting, (3) back‐extraction and (4) second phase splitting—for the recovery of uranium from water. In our conditions, the extraction yield is quantitative and the concentration factor obtained is superior to 100. After stripping with a diluted nitric acid solution (pH < 1), the system can be recycled through a new four‐step cycle. Copyright © 2006 Society of Chemical Industry

Cloud-Point Extraction for Selective Removal of Gd(III) and La(III) with 8-Hydroxyquinoline

:A less-common extraction procedure, cloud-point extraction, is used with a lipophilic chelating agent (8-hydroxyquinoline) to extract and separate lanthanum(III) and gadolinium(lll) ions from an aqueous solution. Surfactant solutions are used in conjunction with 8-hydroxyquinoline to form a lanthanide complex that is extracted into the micellar phase at a temperature above the cloud-point temperature. The structure of the lipophilic part of the nonionic surfactant, the chelating agent-metal molar ratio, and the cloud-point temperature are identified as factors determining the extraction efficiency and selectivity. With Triton X-114, a selectivity higher than 30 and a decontamination factor of 50 for Gd(IlI) indicate that micelle-mediated cloud-point extraction is promising for the specific separation of actinide ions from nuclear waste. Finally, a microwave procedure is proposed to decrease the duration of the experiment to less than 6 min.

Expression of the tetA(C) tetracycline efflux pump in Escherichia coli confers osmotic sensitivity

Expression of tetA(C) in Escherichia coli confers resistance to tetracycline as well as sensitivity to nickel and cadmium salts, lipophilic chelating agents, and aminoglycoside antibiotics. In this report we determine that high-level expression of tetA(C) also confers an osmotic sensitivity. The osmotic-sensitive phenotype is distinct from the tetracycline-resistant phenotype and can be localized to a domain contained within the first 98 amino acid residues of the TetA(C) polypeptide.

Expression of the tetA(C) tetracycline efflux pump in Escherichia coli confers osmotic sensitivity.

Expression of tetA(C) in Escherichia coli confers resistance to tetracycline as well as sensitivity to nickel and cadmium salts, lipophilic chelating agents, and aminoglycoside antibiotics. In this report we determine that high-level expression of tetA(C) also confers an osmotic sensitivity. The osmotic-sensitive phenotype is distinct from the tetracycline-resistant phenotype and can be localized to a domain contained within the first 98 amino acid residues of the TetA(C) polypeptide.

EDTA and DTPA analogues of dipalmitoylphosphatidylethanolamine as lipopphilic chelating agents for metal labeling of LDL

Two lipophilic chelating agents (L) prepared by reaction of dipalmitoylphosphatidylethanolamine with the bis(anhydride) form of ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA) were characterized. L, indium-L or gadolinium-L complexes are soluble in buffered solutions and may be used for metal labeling of LDL.

Cloud‐point extraction of trace copper in lipophilic complex form

Abstract A less‐common extraction procedure, cloud‐point extraction, was used with a lipophilic chelating agent (LEX® 54) to extract copper ion from aqueous solution. Surfactant solutions [0.2–2.2 %(w/w) of nonylphenoxypoly(ethylenoxy)ethanol] with a cloud‐point of 48–52°C, was used in conjunction with a lipophilic chelating agent, dodecyl benzoylacetone, RC6H4CO‐CH2COCH3, to form a copper complex that would be extracted into the micellar phase. Extraction was optimal in a pH range of 5–11 with 95.5–98.6% of the copper extracted. The partition coefficient increased with increasing copper concentration and was in excess of 1000 when the initial copper concentration was 80 ppm. Unlike the cloud‐point temperature and the extraction rate, extraction efficiency was only slightly related to surfactant concentration.

Copper-induced tissue factor expression in human monocytic THP-1 cells and its inhibition by antioxidants.

Transition metals such as copper are known to initiate free radical formation and lipid peroxidation. Recent reports suggest that intracellular reactive oxygen intermediates can induce the transcription of a number of important genes. The present study examines the effects of copper and iron on the ability of monocytic cells to synthesize and express tissue factor, the potent procoagulant factor. Exposure of human monocytic THP-1 cells to 5 to 10 mumol/L Cu2+ led to cell damage and the expression of tissue factor activity to levels up to 70 times higher than control, as measured by a single-stage plasma coagulation assay. These effects were seen only in the presence of a lipophilic chelating agent, 8-hydroxyquinoline, suggesting that intracellular transport of Cu2+ was required. The effects of Cu2+ were mimicked by ceruloplasmin but not by Fe3+ or hemin. The induction of tissue factor activity by Cu2+ was slow in onset (6 hours) but sustained (24 hours) and was accompanied by increased tissue factor mRNA levels, measured by reverse transcription/polymerase chain reaction after annealing with oligomer primers. Increases in tissue factor protein, measured by a specific immunoassay, also occurred but were smaller than those in activity. Cu2+, therefore, appears to act at both the transcriptional and posttranslational levels. The effects of Cu2+ were inhibited by a number of lipophilic antioxidants, including probucol, vitamin E, butylated hydroxytoluene, and a 21-aminosteroid, U74389G. Exposure of monocytes to oxidizing conditions may lead to the expression of high levels of tissue factor activity, with accompanying risk for disseminated intravascular coagulation, and this may be inhibited by lipophilic antioxidants.

Alleviation of nickel-induced biochemical alterations by chelating agents

The effect of 1,4,8,11-tetraazacyclotetradecane (Cyclam), triethylenetetramine (TETA), reduced glutathione (GSH), ethylenediamine tetraacetic acid (EDTA), cyclohexanediamine tetraacetic acid (CDTA), diethylene triamine pentaacetic acid (DTPA), and hydroxyethylenediamine triacetic acid (HEDTA) on the alleviation of nickel-induced biochemical and trace-metal alterations in serum, liver, and kidney of nickel-treated rats was studied. The lipophilic chelating agents Cyclam and TETA exhibited a higher order of effectiveness in alleviating nickel-induced alterations compared to EDTA, CDTA, DTPA, and HEDTA, the hydrophilic chelating agents. The higher efficacy of lipophilic agents may be due to their ability to bind to nickel present in extracellular fluid as well as in intracellular fluid, while the hydrophilic agents may bind only to nickel present in extracellular fluid. Our data also suggest that the efficacy of Cyclam to ameliorate nickel-induced alterations is exceptionally high.

Alleviation of Nickel-Induced Biochemical Alterations by Chelating Agents

Alleviation of Nickel-Induced Biochemical Alterations by Chelating Agents. Misra, M., Athar, M., Hasan, S. K., and Srivastava, R. C. (1988). Fundam. Appl. Toxicol 11, 285–292. The effect of 1,4,8,11-tetraazacyclotetradecane (Cyclam), triethylenetetramine (TETA), reduced glutathione (GSH), ethylenediamine tetraacetic acid (EDTA), cyclohexanediamine tet-raacetic acid (CDTA), diethylene triamine pentaacetic acid (DTPA), and hydroxyethylenedia-mine triacetic acid (HEDTA) on the alleviation of nickel-induced biochemical and trace-metal alterations in serum, liver, and kidney of nickel-treated rats was studied. The lipophilic chelating agents Cyclam and TETA exhibited a higher order of effectiveness in alleviating nickel-induced alterations compared to EDTA, CDTA, DTPA, and HEDTA, the hydrophilic chelating agents. The higher efficacy of lipophilic agents may be due to their ability to bind to nickel present in extracellular fluid as well as in intracellular fluid, while the hydrophilic agents may bind only to nickel present in extracellular fluid. Our data also suggest that the efficacy of Cyclam to ameliorate nickel-induced alterations is exceptionally high.

Influence of chelating agents on the distribution and excretion of cadmium in rats

The effects of the chelating agents CaNa 2-ethylenediaminetetraacetate (EDTA), CaNa 3-diethylenetriaminepentaacetate (DTPA), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropanol (BAL), and 2,3-dimercaptopropane-1-sulfonate (DMPS) and of the lipophilic chelating agents Puchel, Puchel-bisamidocysteineethyl ester (Puch-D), and EDTA-bis-amidocysteineethyl ester (EDTA-D) on the distribution of iv injected Cd were studied in male Sprague-Dawley rats. The chelating agents were injected iv as single doses given 10 sec, 1 hr, or 3 hr after 3 μmol/kg Cd + 115mCd. When the chelating agents were injected within 10 sec after the metal, all agents reduced the total body cadmium burden by varying extents ranging from 3% of that in untreated control rats after 0.01 mmol BAL/kg to 94% following 0.1 mmol DTPA/kg. When given 1 hr after Cd injection, the efficacy of all the agents tested was markedly reduced or abolished; at this time only Puchel and Puc 3h-D provoked significant reductions in the body burden of Cd by 21 and 32%, respectively. When treatment was delayed until 3 hr after Cd injection, only Puch-D was able to reduce the body and liver burden of the metal by 14 and 9%, respectively. Combined treatment with Puchel + DTPA, BAL + DTPA, or BAL + DMPS did not enhance Cd removal to an extent greater than that expected from the equivalent dose of the more effective agent of that pair alone. Repeated administration of DTPA, 20 × 0.1 mmol/kg, during 4 weeks by ip or po administration of the same dose in the drinking water over 4 weeks, was no more effective than the first dose of the chelating agent alone. Gel chromatographic studies of the distribution of Cd among the proteins of the liver cytosol in treated and untreated animals indicate that neither DTPA nor Puchel was able to release Cd from the metallothionein complex.

Positive selection for loss of tetracycline resistance.

A simple technique has been devised that allows direct plate selection of tetracycline-sensitive clones from a predominantly tetracycline-resistant population. The technique is especially useful in genetic methodologies based on the use of tetracycline resistance transposons, such as Tn10. Potential uses of the method include selection of deletion mutants, fine-structure mapping, generalized mapping, construction of multiply marked strains, elimination of tetracycline resistance transposons and plasmids and cloning. The technique is based on our finding that tetracycline-resistant cells are hypersensitive to lipophilic chelating agents, such as fusaric acid. This finding supports the contention that certain metal ions critically facilitate tetracycline uptake and leads us to suggest possible molecular mechanisms for tetracycline resistance.

Nuclear mutations conferring oligomycin resistance in Neurospora crassa.

Mutants of Neurospora crassa have been isolated that are highly resistant to inhibition by oligomycin, an inhibitor of mitochondrial ATPase activity. Dixon plots (Dixon, M., and Webb, E.C. (1964) Enzymes, 2nd Ed, pp. 328-330, Academic Press, New York) of oligomycin inhibition curves of the parent strain and the resistant mutants are linear, indicating that oligomycin interacts at a single site within the ATPase complex. The Ki values obtained from the mutants vary from 150 to 900 times greater than the Ki obtained for the parent strain. The parent strain and the oligomycin-resistant mutants are also inhibited by bathophenanthroline, a lipophilic chelating agent that inhibits F1 ATPase activity. Dixon plots of bathophenanthroline inhibition curves are also linear and Ki values obtained are all approximately equal. Crosses of the oligomycin-resistant mutants to the oligomycin-sensitive parent strain show a mendelian segregation of the resistance characteristic. These data show that mutations leading to oligomycin resistance in Neurospora are due to alterations in nuclear genes.