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PubMed1983

DL- and meso-dimercaptosuccinic acid: in vitro and in vivo studies with sodium arsenite.

Dimercaptosuccinic acid (DMSA) has been receiving increasing interest as an antidote for poisoning by heavy metals. Of the various isomeric forms, meso-DMSA has been studied most extensively because its preparation and purification are relatively easy. Using a variety of in vitro and in vivo procedures, we have investigated and compared DL- and meso-DMSA as antidotes for sodium arsenite. The two forms of DMSA are equally effective in preventing or reversing, in vitro, the arsenite inhibition of the activity of mouse kidney pyruvate dehydrogenase (PDH) complex, DL-DMSA, however, is superior to meso-DMSA for the in vivo reversal of PDH activity as measured in vitro. The LD50 values of DL- and meso-DMSA in the mouse were 10.84 and 13.73 mmol/kg, ip, respectively. The ED50 values of the two DMSA forms were not significantly different in mice receiving a LD99 dose of sodium arsenite. DL- and meso-DMSA were equally effective in mobilizing tissue 74As of rabbits. The activity of DMSA as an arsenic antidote appeared to be independent of its isomeric structural configuration. There did not appear to be any great advantage in using DL-DMSA instead of meso-DMSA as an arsenic antidote.

Animals↗
PubMed1985

Dimercaptan metal-binding agents influence the biotransformation of arsenite in the rabbit.

The urinary metabolites of sodium arsenite have been investigated in rabbits given sodium arsenite and water-soluble dimercaptans. Rabbits injected sc with NaAsO2 (1 mg As/kg) were given, im 1 hr later, either saline, 2,3-dimercapto-1-propanesulfonic acid (DMPS), mesodimercaptosuccinic acid (DMSA), or N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA) at 0.2 mmol/kg. Arsenic metabolites in urine collected from treated rabbits were isolated by combined anion-cation-exchange chromatography. Column fractions were acid-digested and analyzed for arsenic by direct hydride-flame atomic absorption spectrophotometry. The relative amounts of inorganic arsenic, methylarsonate, and dimethylarsinate found in 0 to 24 hr urine of rabbits given only sodium arsenite agreed closely with those reported for human subjects given arsenite po. This finding suggests that the rabbit biotransforms arsenite in a manner very similar to that of man. The urinary excretion of total arsenic between 0 and 24 hr was elevated after dimercaptan administration, but urinary excretion of total arsenic between 0 and 48 hr was unaffected. This result indicates that the action of these dimercaptans occurs early after treatment. In addition, the dimercaptans influenced differently the amounts of the arsenic metabolites excreted in the urine between 0 and 24 hr. DMPS, DMSA, or DMPA increased arsenite excretion but decreased dimethylarsinate excretion. DMPS or DMPA treatment increased methylarsonate excretion but DMSA did not. Arsenate excretion increased after DMPS or DMSA treatment but was not affected by DMPA treatment. These results suggest that the dimercaptans, in addition to increasing arsenic excretion, also influence the biotransformation of arsenite to less toxic species. The different effects on the urinary excretion of arsenic metabolites suggest that these dimercaptan metal binding agents have mechanisms of action in addition to simple chelation of inorganic arsenic.

Animals↗
PubMed1985

Induction of hepatic metallothionein in mouse liver following administration of chelating agents.

Chelating agents commonly used in therapy of heavy metal intoxication alter the levels of essential metals in liver, kidneys, and serum. Induction of metallothionein synthesis in liver occurs following exposure to a variety of chemical and environmental insults and, in some cases, has been attributed to enhanced hepatic uptake of zinc. Therefore, the effect of acute exposure to seven common metal chelators on the concentration of metallothionein in liver was investigated. Adult male Swiss Webster mice were injected intraperitoneally with the chelators and hepatic metallothionein was quantified by the cadmium radioassay. Ethylenediaminetetraacetic acid (EDTA) produced a 5- to 6-fold increase in hepatic metallothionein 24 hr after injection of 0.75 to 3.0 g/kg. No significant increase in hepatic MT was observed until 12 hr following injection of EDTA (1.5 g/kg, ip). Maximal levels were reached between 12 and 48 hr following EDTA injection. Cadmium, a known inducer of hepatic metallothionein, produced a 15-fold increase in the concentration of MT in liver 24 hr following injection. By comparison, 2,3-dimercaptopropanol and diethyldithiocarbamate produced a 9-fold and 13-fold increase in hepatic metallothionein levels, respectively, 24 hr following injection. A 4- to 6-fold increase in metallothionein was observed 24 hr following injection of 2,3-dimercaptosuccinic acid, D,L-penicillamine, diethylenetriaminepentaacetic acid, and EDTA, while nitrilotriacetic acid elevated hepatic metallothionein levels by 2-fold. Alterations in the concentration of hepatic metallothionein by chelators may have implications for their efficacy in the treatment of cadmium intoxication.

Animals↗
PubMed1987

Conditioned flavor aversions: applications in assessing the efficacy of chelators in the treatment of heavy-metal intoxication.

A series of studies investigated the conditioned flavor aversions induced by administration of either lead or thallium in combination with either dimercaprol or dimercaptosuccinic acid in an attempt to correlate changes in flavor-aversion conditioning to changes known to alter the toxicity of metal administration. Rats received po administration of either thallium sulfate or lead acetate given alone or in combination with either dimercaprol or dimercaptosuccinic acid after consuming saccharin. Three days later they were given the choice between consuming saccharin or water, and saccharin preferences were recorded. When compared to rats receiving either nothing or the vehicle, rats receiving either lead or thallium showed significant reductions in saccharin preferences (i.e., conditioned flavor aversions). Rats receiving lead acetate in combination with either of the two chelators displayed significantly reduced conditioned flavor aversions when compared to the aversions induced in rats receiving lead alone. Under the same conditions, there were no differences in the conditioned flavor aversions of rats receiving thallium only and those of rats receiving thallium in combination with either of the two chelators. Attenuation of the lead-induced conditioned flavor aversions was eliminated when chelator administration was delayed by 4 hr. This attenuation of lead-induced but not thallium-induced aversions by dimercaprol and dimercaptosuccinic acid demonstrates the sensitivity and selectivity of the flavor-aversion conditioning paradigm in characterizing metal-chelator interactions and is in agreement with clinical reports of effective chelation therapy in cases of lead but not thallium intoxication.

Analysis of Variance↗
PubMed1988

Esters of meso-dimercaptosuccinic acid as cadmium-mobilizing agents.

The dimethyl, diethyl, di-n-propyl, diisopropyl (Di-PDMS), and di-n-butyl esters of meso-2,3-dimercaptosuccinic acid were prepared by esterification of the parent acid and were subsequently purified and characterized. Their relative ability to mobilize cadmium from its aged (greater than 30 days) deposits was evaluated in mice in comparison with 2,3-dimercapto-1-propanol (BAL). All but the dimethyl ester were superior to BAL in reducing the hepatic cadmium levels, though none was superior in reducing renal cadmium levels. Their efficacy in reducing hepatic cadmium levels had the result that all except the dimethyl ester were significantly more effective than BAL in reducing total cadmium body burdens in mice. The most effective of these compounds, Di-PDMS, caused a reduction of whole body cadmium of 59% (i.e., to 41% of control values) under conditions where the corresponding reduction found for BAL was only 18% (i.e., to 82% of control value). The predominant route of excretion of cadmium subsequent to administration of these compounds is via the fecal route (greater than 99%). A synergistic effect was found in the reduction of whole body and kidney cadmium burdens when Di-PDMS was used in combination with trisodium calcium diethylenethriaminepentaacetate.

Animals↗
PubMed1989

Determination and metabolism of dithiol chelating agents. VIII. Metal complexes of meso-dimercaptosuccinic acid.

Metal complexes of meso-dimercaptosuccinic acid (DMSA) with Pb2+, Cd2+, and Hg2+ were studied by potentiometric and infrared methods. This dimercapto metal-binding agent was found to form complexes whose structures are dependent on the metal ion to be complexed. In the cases of Pb2+ and Cd2+, one oxygen and one sulfur act as the donor atoms; in the case of Hg2+, two sulfur atoms act as the donors. The solubilities of all metal chelates were found to be pH dependent. Complexes of cadmium and lead are insoluble in the pH range 1.0 to 7.1, but are solubilized when the noncoordinated sulfhydryl and carboxylic acid groups are ionized. The mercury complex is insoluble in the pH range 1.0 to 3.0. It dissolves when one of the noncoordinated carboxylic acid groups is ionized. The dimethyl ester of meso-DMSA (DiMe-meso-DMSA) was synthesized and its acid dissociation constants were determined (pK1 = 6.38 and pK2 = 8.00). Esterification of the carboxyl groups of meso-DMSA changes its coordination properties in that the two sulfur atoms of DiMe-meso-DMSA are used to coordinate with Hg2+, Cd2+, or Pb2+. Esterification of meso-DMSA also changes its biological properties. DiMe-meso-DMSA, when given to rats 3 days after Cd administration, greatly increased the excretion of Cd via bile. In contrast, meso-DMSA was devoid of such activity.

Animals↗
PubMed1989

Influence of 2,3-dimercaptosuccinic acid on gastrointestinal lead absorption and whole-body lead retention.

2,3-Dimercaptosuccinic acid (DMSA) is a new orally active heavy metal chelator for the treatment of childhood Pb intoxication on an outpatient basis. The influence of DMSA, as well as other chelating agents, on gastrointestinal 203Pb absorption and whole-body 203Pb retention was examined. Groups of Sprague-Dawley rats (230-260 g) were gavaged with a solution containing approximately 25 mg/kg Pb [as Pb(NO3)2] plus 15 microCi 203Pb. Some groups were then immediately given 0.11 mmol/kg of either DMSA, CaNa2EDTA, D-penicillamine, or BAL by oral gavage, while other groups received the same drugs by ip injection. Control groups received solutions of the drug vehicles po or ip. Whole-body Pb retention and gastrointestinal Pb absorption (whole body retention + urinary Pb excretion) were significantly decreased in rats that received DMSA po. This finding implies that the use of DMSA to treat childhood lead intoxication on an outpatient basis is not associated with a risk for increased Pb absorption.

Administration, Oral↗
PubMed1989

The mobilization of intracellular cadmium by butyl and amyl esters of meso-2,3-dimercaptosuccinic acid.

The esters of the general structure, [CH(SH)COOR]2, i.e., Di-BDMS, R = CH2CH(CH3)2; Ds-BDMS, R = CH(CH3)CH2CH3; Di-ADMS, R = CH2CH2CH(CH3)2; and D3-ADMS, R = CH(CH2CH3)2 from the reaction of meso-2,3-dimercaptosuccinic acid with isobutyl, sec-butyl, isoamyl, and 3-amyl alcohols, respectively, have been prepared, characterized, and examined as chelating agents for the removal of cadmium from its aged intracellular deposits. All of these compounds depleted cadmium from such deposits and significantly reduced the whole body levels of cadmium. In the case of three (Ds-BDMS, Di-BDMS, and Di-ADMS) of these compounds, the reductions achieved are equal to or greater than that produced by 2,3-dimercapto-1-propanol (BAL) under similar circumstances. None of these compounds caused any redistribution of cadmium to the brain, and two of them (Di-BDMS and Di-ADMS) caused a very much larger reduction in the liver levels of cadmium than BAL. None was as effective as BAL in reducing kidney levels of cadmium. These compounds are not soluble in water and are administered as solutions in peanut oil. A comparison of the behavior of these compounds with others which have been reported to be effective in reducing body burdens of cadmium in chronic cadmium intoxication reveals that they are among the most effective. An analysis of the manner in which mobilizing efficacy changes with structure indicates that higher, purely alkyl analogs are not expected to be superior to these compounds, though other structural variations may be.

Animals↗
PubMed1989

Determination and metabolism of dithiol chelating agents. VI. Isolation and identification of the mixed disulfides of meso-2,3-dimercaptosuccinic acid with L-cysteine in human urine.

Virtually nothing is known about the biotransformation of the heavy metal chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA). Two fasted, normal, young men were given 10.0 mg DMSA/kg po, and their urines were collected over a 14-hr period. Urine samples were analyzed, before and after electrolytic reductive treatment, for DMSA and its biotransformants using bromobimane derivatization, HPLC separation, and fluorescence detection. Metabolites were isolated by HPLC, ion-pairing extraction, ion-exchange extraction, and TLC. By 14 hr after DMSA administration, 87% of the total DMSA and 95% of the total L-cysteine found in urine consisted of altered forms of these compounds. The urinary excretion of altered DMSA, at 1, 2, 4, 6, 9, and 14 hr after administration of DMSA, when compared to the urinary excretion of altered L-cysteine had a correlation coefficient of 0.952 and p less than 0.003. Approximately 90% of the altered DMSA excreted in the 2- to 4-hr urine was found in disulfide linkage with L-cysteine. The remaining 10% was found as cyclic disulfides of DMSA. Of the mixed disulfides found in 4- to 6-hr urine, 97% consisted of two L-cysteine residues per one DMSA and the remaining 3% consisted of one L-cysteine per one DMSA. The 2:1 mixed disulfides (97%) were isolated as three distinct species by TLC, consisting of 77, 12, and 8% of the total mixed disulfides found. In addition to the novelty of these biotransformants of DMSA, the DMSA-cysteine mixed disulfides indicate a thiol-disulfide interchange between DMSA and L-cystine. The discovery of the formation of these water soluble DMSA-cysteine mixed disulfides should encourage the evaluation of DMSA in the treatment of cystinuria.

Adult↗
PubMed1990

The mobilization of intracellular cadmium by alkoxyethyl esters of meso-2,3-dimercaptosuccinic acid.

The cadmium mobilizing properties of two newly synthesized esters of meso-2,3-dimercaptosuccinic acid in mice have been examined. They are: di(2'-methoxyethyl) meso-2,3-dimercaptosuccinate ([-CH(SH)COOCH2CH2OR]2, R = CH3; MEDMS), and di(2'-ethoxyethyl) meso-2,3-dimercaptosuccinate ([-CH(SH)COOCH2CH2OR]2, R = CH2CH3; EEDMS), conveniently prepared from dimercaptosuccinate acid with 2-methoxyethanol and 2-ethoxyethanol, respectively. Mobilization studies in mice of aged in vivo cadmium deposits using five ip injections of 0.40 mmol/kg of each chelator in peanut oil clearly indicate that both compounds, MEDMS and EEDMS, are significantly superior to 2,3-dimercaptopropan-1-ol (BAL) in depleting the whole body burden of cadmium. The reductions caused by MEDMS and EEDMS were approximately 20 and 26%, respectively, whereas under similar dosage regimens BAL effected about only a 12% reduction. The esters were neither equal nor superior to BAL for the reduction of renal cadmium levels, MEDMS being the least effective. For the mobilization of hepatic cadmium deposits, both were quite promising (MEDMS, 20%; EEDMS, 34% reduction) compared to BAL (only 2% reduction). There was no accumulation of cadmium with either MEDMS or EEDMS in any of the other organs examined--spleen, testes, pancreas, and particularly the brain. These compounds enhance the fecal excretion of cadmium by a factor of 25- to 40-fold but have very little effect on the urinary excretion of this element. The present study reveals that the order of overall efficacy is EEDMS greater than MEDMS greater than BAL, considering the liver and whole body burdens of cadmium, but BAL greater than EEDMS greater than MEDMS in terms of the efficacy in reducing cadmium levels in the kidneys.

Animals↗
PubMed1991

Evidence for arsenic as the immunosuppressive component of gallium arsenide.

Gallium arsenide (GaAs) has been shown previously to suppress the in vivo antibody-forming cell (AFC) response to sheep erythrocytes (SRBC) when administered intratracheally at concentrations between 50 and 200 mg/kg. In the present studies, direct addition of GaAs to in vitro-generated antibody cultures resulted in dose-dependent suppression of the primary antibody response, and was only seen when GaAs was added within 36 hr following immunization. Using atomic absorption spectrophotometry on tissue samples from mice exposed to 200 mg/kg GaAs, arsenic concentrations were found to peak in the spleen at 24 hr and decline, whereas gallium concentrations continue to rise through 14 days. Concentrations of each metal in the spleen at 24 hr are comparable to the concentrations achieved for each metal when GaAs is added at 25 microM to the in vitro model system. The 24 hr time point was chosen for comparison because all in vivo-in vitro studies were conducted using spleens from mice 24 hr after GaAs exposure. NaAsO2 and Ga(NO3)3 suppressed the AFC response dose-dependently, and in a time-dependent manner similar to GaAs when added to the in vitro system. However, based on IC50 values for each salt, the role of the gallium component in the immunosuppression appears weak. Oxalic acid (OA) and meso-2,3-dimercaptosuccinic acid (DMSA), chelators of gallium and arsenic respectively, were added to cultures with GaAs to confirm that arsenic was the primary immunosuppressive component. DMSA dose-dependently blocked GaAs-induced immunosuppression in vitro, while OA had no effect. The metal-binding compounds were determined to be specific for the metals used in these studies and did not cross-react with one another. DMSA was evaluated for its ability to prevent suppression of the AFC response in splenocytes from GaAs-exposed mice and was able to block GaAs-induced suppression of the AFC response when given sc every 4 hr beginning 1 hr prior to GaAs exposure. These data indicate that the arsenic component of GaAs is the major contributor to the GaAs-induced immunosuppression and that this effect occurs within the first 36 hr of the 5-day culture period in a concentration-dependent manner.

Animals↗
PubMed1992

Stable isotopic tracers of lead mobilized by DMSA chelation in low lead-exposed rats.

The ability of DMSA to mobilize skeletal lead or effect a redistribution of endogenous lead to other target organs in low lead-exposed organisms is unclear. Discrepant results of past studies of DMSA and other lead chelators (e.g., CaNa2EDTA) may be due, in part, to experimental differences and difficulties in distinguishing mobilized skeletal lead from other endogenous or exogenous lead sources. Therefore, the influence of DMSA on the mobilization and redistribution of lead in skeletal and soft tissue compartments of low lead-exposed female Wistar (115-125 g) rats was investigated using ultraclean stable lead isotope tracer techniques. Rats that had been reared on a low lead-level diet (lead intake approximately 80 ng Pb/g body/day) were fed 206Pb-enriched drinking water (210 ng Pb/ml) for 1.5 days and then were chelated with a single ip injection of a 0.11 mmol/kg dose of DMSA. Blood, kidney, brain, tibia, urine and feces were collected 24 hr after chelation and analyzed for lead concentrations by graphite furnace atomic absorption spectrometry and for lead isotopic compositions by thermal ionization mass spectrometry. These analyses demonstrated that DMSA chelation significantly increased (15-fold) the diuresis of labile soft tissue lead, but not skeletal lead. DMSA also appeared to effect a redistribution and input of a comparable amount of lead to the skeleton and smaller relative amounts of lead to the soft tissues (blood, kidney) of the chelated animals. The clinical significance of these latter observations beyond the context of this preliminary study is not clear.

Animals↗