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PubMed1990

Evaluation of the developmental effects on mice after prenatal, or pre- and postnatal exposure to 2,3-dimercaptopropane-1-sulfonic acid (DMPS).

The sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS), a water soluble metal complexing agent, was administered to four groups of pregnant Swiss mice at 0, 70, 210, and 630 mg/kg/day by two dosing schedules: gestation day 14 until birth (prenatal exposure), and gestation day 14 until postnatal day 21 (pre- and postnatal section). Dams were allowed to deliver and the number of live and dead pups recorded. Each pup was sexed and weighed on days 0, 4, 14, and 21. Also, pinna detachment, incisor eruption and eye opening were monitored. No adverse effects on offspring survival or development were evident in either exposures at doses employed in this study. The "no observable effect level" (NOEL) for health hazard to the developing fetus or pup was 630 mg DMPS/kg/day. This dose is much higher than the amounts of DMPS usually administered in human heavy metal poisoning.

Animals↗
PubMed1984

Chelation of lead by dimercaptopropane sulfonate and a possible diagnostic use.

The mobilization of lead (Pb) from Pb-exposed rats was examined following administration of dimercaptopropane sulfonate (DMPS). A dose-response study showed that the highest dose of DMPS (200 mumol/kg, ip) removed Pb from kidneys, liver, and bone, while the lower doses (25 and 50 mumol/kg) chelated Pb only from the kidneys. In experiments where DMPS was repeatedly injected to Pb-exposed rats, the maximum urinary excretion of Pb was observed within 24 hr after the first injection, with little effect in subsequent injections. Discontinuation of DMPS after the first injection (at a dose of 50 mumol DMPS/kg) caused renal Pb levels to increase until further injection of DMPS, several days later, which again mobilized Pb only from the kidneys. A single oral administration of 150 mumol DMPS/kg (a dose adjusted for specific chelation from the kidney) to rats, previously exposed to different doses of Pb resulted in a significant decrease of renal Pb in groups injected with more than 0.5 mg Pb/kg. A linear relationship was observed between renal Pb burden and urinary Pb excretion following chelation (r = 0.94, p less than 0.01). Thus, the specific removal of Pb from the kidney by DMPS treatment suggests a potential use of DMPS, a relatively nontoxic drug, for the estimation of renal Pb burden and also for treatment of Pb poisoning. Unlike other chelating agents, DMPS can be administered orally.

Administration, Oral↗
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↗
PubMed1982

Biological chelation: 2,3-dimercapto-propanesulfonic acid and meso-dimercaptosuccinic acid.

Water soluble analogs of British Anti-Lewisite that are active orally and less toxic than BAL are now available. These agents are 2,3-dimercapto-1-propanesulfonic acid and meso-dimercaptosuccinic acid. Evidence for their effectiveness in preventing the lethal effects of sodium arsenite in mice and lewisite in rabbits is presented. These analogs can be expected to replace BAL in the treatment of heavy metal poisoning.

Animals↗
PubMed1992

Amelioration by BAL (2,3-dimercapto-1-propanol) and DMPS (sodium 2,3-dimercapto-1-propanesulfonic acid) of arsenite developmental toxicity in mice.

Inorganic arsenic is embryotoxic and teratogenic in chicks, golden hamsters, mice, and rats. Certain dithiol chelators have been reported to protect against arsenite-induced lethality and to decrease arsenic body burden. The present study evaluated the influence of BAL (2,3-dimercapto-1-propanol) and DMPS (sodium 2,3-dimercapto-1-propanesulfonic acid), a water-soluble analogue of BAL, on arsenic-induced embryotoxic and teratogenic effects in the mouse. A series of four BAL or DMPS injections was administered sc to pregnant mice immediately after a single ip injection of 12 mg/kg of sodium arsenite given on Day 9 of gestation and at 24, 48, and 72 hr thereafter. Controls received sc corn oil with or without arsenite. Amelioration by BAL and DMPS of arsenite developmental toxicity was assessed at 15, 30, and 60 mg/kg/day, and 75, 150, and 300 mg/kg/day, respectively. BAL given following arsenite was not able to ameliorate the developmentally toxic effects of arsenite seen in mice, whereas treatment with DMPS at 150 and 300 mg/kg showed significant protective effects against arsenite embryotoxicity and teratogenicity. DMPS administration at 300 mg/kg also protected the dams against arsenite-induced maternal toxicity.

Animals↗
PubMed1984

DMSA, DMPS, and DMPA--as arsenic antidotes.

meso-Dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propanesulfonic acid, Na salt (DMPS), and N-(2,3- dimercaptopropyl )- phthalamidic acid (DMPA) are water soluble analogs of 2,3-dimercapto-1-propanol (BAL). The relative effectiveness or therapeutic index of these dimercapto compounds in protecting mice from the lethal effects of an LD99 of sodium arsenite is DMSA greater than DMPS greater than DMPA greater than BAL in the magnitude of 42:14:4:1, respectively. DMPS, DMPA, or DMSA will mobilize tissue arsenic. BAL, however, increases the arsenic content of the brain of rabbits injected with sodium arsenite. These results raise the question as to the appropriateness of BAL as the treatment for systemic arsenic poisoning. Either DMSA or DMPS, when given sc or po, will protect rabbits against the lethal systemic effects of subcutaneously administered Lewisite . DMPS and DMSA have promise as prophylactics for the prevention of the vesicant action of Lewisite . The sodium arsenite inhibition of the pyruvate dehydrogenase (PDH) complex can be prevented and reversed in vitro or in vivo by DMPS, DMSA, DMPA, or BAL. Of them all, DMPS is most potent and BAL appears to be the least potent. The usefulness of all these dimercapto compounds would be enhanced by a careful study of their metabolism and biotransformation. These dimercapto compounds are in a great many respects orphan drugs. At this stage of their development, it is very difficult for the clinician to obtain funds to study them clinically even though they appear to be useful for treatment of poisoning by any one of the heavy metals.

Animals↗
PubMed1990

Determination and metabolism of dithiol chelating agents. VII. Biliary excretion of dithiols and their interactions with cadmium and metallothionein.

N-(2,3-Dimercaptopropyl) phthalamidic acid (DMPA), meso-dimercaptosuccinic acid (DMSA), and 2,3-dimercapto-1-propanesulfonic acid (DMPS) are dithiol chelating agents with antidotal activity for lead, mercury, arsenic, and other heavy metals. The biliary excretion of these compounds was studied in male Sprague-Dawley rats. After iv administration of DMPA, 72% of the injected dose was recovered in the bile. Half of the recovered DMPA was in the unaltered form (parent compound) and the other half was in the altered form (parent compound recovered after chemical reduction by DTT). An altered, presumably disulfide, form of DMPS was found in the bile. Neither unaltered nor altered DMSA was detected in the bile. DMPA (0.10 mmol/kg), given to rats 3 days after exposure to Cd, elicited within 30 min a 20-fold increase in biliary Cd excretion. The increase of biliary Cd by DMPA was dose-related and not due to an increase of bile flow rate. DMSA and DMPS did not significantly affect the biliary excretion of Cd. Incubation of DMPA or DMSA with Cd-saturated metallothionein (MT) resulted in the removal of Cd from MT. DMPA was more active than DMSA in this respect. The evidence strongly supports the mechanism that the increase of biliary cadmium following DMPA administration is the result of DMPA entering cells and mobilizing and removing the cadmium from MT. The removal of cadmium from metallothionein by dithiol chelating agents provides another dimension to their mechanisms of action and may provide an important new tool for the study of cadmium as well as metallothionein.

Animals↗
PubMed1987

tri-n-Butyltin: a membrane toxicant.

Increased use of the biocidal compound tri-n-butyltin (TBT) in antifouling paints has prompted research aimed at determining the mechanism for TBT toxicity. Past investigations indicate that the primary cellular target for TBT is the cell membrane. Erythrocyte suspensions treated with TBT concentrations 2 greater than or equal to 5 microM undergo hemolysis described by a sigmoidal kinetic pattern. Transformation of cell shape from discocyte to echinocyte occurs at TBT concentrations greater than or equal to 0.1 microM, indicating that the compound enters the outer membrane bilayer. TBT at concentrations greater than or equal to 10 microM forms electron-dense aggregates that are intercalated within plasma membranes as viewed in ultrathin sections by transmission electron microscopy. Qualitative X-ray microanalysis of these aggregates confirms the presence of tin. The size of these structures can be modified by either 10 mM cyanide or 2,3-dimercaptopropanol (British Anti-Lewisite, BAL). Adding 10 mM cyanide to hemolytic TBT concentrations resulted in a synergistic stimulation of hemolysis attributable to high cyanide anion concentrations in or near the cell membrane. The elevated cyanide anion levels are thought to contribute to membrane lysis. The lipophilic dimercapto compounds BAL, dithiothreitol, and 2,3-dimercaptosuccinate are effective inhibitors of TBT-induced lysis. Water-soluble 2,3-dimercapto-1-propane sulfonate, a BAL analog, was largely ineffective as an inhibitor. The detailed molecular mechanism for TBT-induced membrane lysis is not yet clear. Cellular ATP depletion could be induced by TBT as well as by delipidation of anionic phospholipids or even formation of tributylstannylperoxy radicals, resulting in lipid peroxidation.

Chemical Phenomena↗
PubMed1989

Influence of 2,3-dimercaptopropane-1-sulfonate and dimercaptosuccinic acid on the mobilization of mercury from tissues of rats pretreated with mercuric chloride, phenylmercury acetate or mercury vapors.

The efficiency of the sodium salt of 2,3-dimercaptopropanesulfonic acid (DMPS) and meso-dimercaptosuccinic acid (DMSA) to mobilize mercury from tissues has been assessed in rats pretreated with different doses of HgCl2, phenylmercury acetate or exposed to different concentrations of mercury vapors. These pretreatments increase the mercury concentration in the kidney and to a lower extent in the liver. Only exposure to metallic mercury vapor leads to mercury accumulation in the brain. Both chelators mobilize mercury stored in the kidney and the amount of metal excreted in urine following a single administration of DMSA is a good indicator of the renal burden of mercury. The rate of removal is greater after DMPS administration than after DMSA but repeated administration of either agents eventually leads to the same total amount of mercury mobilized from the kidney. The loss of mercury from the liver can be slightly accelerated by repeated administration of the chelators. However, the chelators are inefficient in removing mercury from the brain.

Administration, Inhalation↗
PubMed1990

Evaluation of the developmental toxicity of 2,3-dimercapto-1-propanesulfonate (DMPS) in mice. Effect on mineral metabolism.

The sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS), a potent chelating agent used in the treatment of inorganic and organic heavy metal intoxications was evaluated for developmental toxicity in pregnant Swiss mice. DMPS was administered by gavage at doses of 0, 75, 150 and 300 mg/kg per day on gestational days 6-15. Females were evaluated for body weight gain, food consumption, appearance and behavior, survival rates and reproduction data. Cesarean sections were performed on gestation day 18. There were no maternal toxic effects, and no treatment-related changes were recorded in the number of total implants, resorption, the number of live and dead fetuses, fetal body weight or fetal sex distribution data. Gross external, soft tissue and skeletal examination of the DMPS-treated fetuses did not show significant differences at any dose in comparison with the controls. Mineral analysis of maternal and fetal tissues revealed slight effects of DMPS on metabolism of calcium, magnesium, zinc, copper and iron. The results of this study in mice indicate that DMPS is not a developmental toxicant at levels up to 300 mg/kg per day.

Abnormalities, Drug-Induced↗
PubMed1992

Characterization of gold in urine and bile following administration of gold sodium thiomalate with chelating agents to rats.

Gold was characterized in the urine and bile of rats treated with D-penicillamine (D-PEN), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropane sulphonate (DMPS), or N-(2-mercapto-2-methylpropanoyl)-L-cysteine (bucillamine) immediately after gold sodium thiomalate (AuTM) injection by both gel chromatographic and electrophoretic methods. It is suggested that the gold in the urine and bile after AuTM administration was predominantly bound to high molecular weight compounds. The characterization of gold in the urine after administration of AuTM with D-PEN, DMSA, or DMPS showed that most of the gold was bound to the chelating agents. In the treatment with the chelating agents such as D-PEN and DMPS, the gold was mainly excreted as a gold-chelating agent compound in the bile and a minor portion of the gold was present in the form of a gold-L-cysteine compound and high molecular weight compounds. DMSA treatment showed that a major portion of the gold was bound to high molecular weight compounds in the bile and a minor portion of the gold was present in the forms of gold-DMSA and gold-L-cysteine compounds. The administration of AuTM and bucillamine indicated that the gold was mainly present as a gold-Me-bucillamine compound in the urine and a gold-bucillamine compound in the bile.

Animals↗
PubMed1993

meso-2,3-dimercaptosuccinic acid monoalkyl esters: effects on mercury levels in mice.

Seven monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) were evaluated for relative activities in mobilizing and promoting excretion of mercury in mercury-laden mice. Compounds assessed were the ethyl (M-EDMS), n-propyl (Mn-PDMS), isopropyl (Mi-PDMS), n-butyl (Mn-BDMS), isobutyl (Mi-BDMS), n-amyl (Mn-ADMS), and isoamyl (Mi-ADMS) esters. 2,3-Dimercaptopropane-1-sulfonate (DMPS) and DMSA were used as positive controls. After the first oral dose of each compound at 0.5 mmol/kg, DMSA and DMPS reduced the corporal mercury burden 16% and 24%, respectively, compared to controls, while the monoesters effected reductions of 35% (M-EDMS) to 49% (Mi-ADMS). After the second treatment at the same dose, the respective reductions produced by DMSA and DMPS were 24% and 38%, and those conferred by the monoesters ranged from 52% (M-EDMS) to 61% (Mn-BDMS). Determination of the comparative dose-response relationships of DMSA and Mi-ADMS on corporal and renal mercury concentrations revealed the monoester to be more active than DMSA on both parameters at each dose used. The cumulative amount of mercury excreted in urine by control mice over a 3-day period was 7.08 micrograms; this was increased 22%, 85%, and 94% by daily i.p. injections of DMSA, DMPS, and Mi-ADMS, respectively, at a daily dose of 0.1 mmol/kg. The respective cumulative 3-day totals recovered in feces from control mice and from mice treated with DMSA, DMPS, and Mi-ADMS were 9.76, 8.21, 10.44, and 11.73 micrograms. Parallel daily measurements of retained whole body radioactivity from 203Hg in mice were in good agreement with the values calculated from the excretion data.

Animals↗
PubMed1995

Effects of meso-2,3-dimercaptosuccinic acid or 2,3-dimercaptopropane 1-sulfonate on beryllium-induced biochemical alterations and metal concentration in male rats.

The effects of two chelating agents, meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane 1-sulfonate (DMPS) on the mobilization, distribution, hepatic and hematopoietic toxicity of beryllium were compared in male rats exposed to beryllium. Animals were exposed to beryllium nitrate (0.5 mg/kg, orally, daily 5 days/week) for 21 days. Twenty-four hours after the last dose they were injected with a chelating agent (DMSA or DMPS) (25 or 50 mg/kg, twice daily for 5 days). The administration of DMSA and DMPS at a dose of 50 mg/kg marginally elevated the fecal excretion of beryllium. DMPS was effective in depleting beryllium from the liver, spleen and kidneys. However, DMPS (50 mg/kg) results in the redistribution of beryllium to blood. Beryllium-induced inhibition of hepatic alkaline phosphatase and hepatic adenosine triphosphatase (ATPase) were restored considerably with the chelating agents. Also, hepatic and renal histopathological lesions were less marked in rats treated with DMPS (50 mg/kg) compared with those treated with beryllium per se and DMSA. These effects were more prominent at the 50-mg/kg dose of chelating agents than at 25 mg/kg. These results suggest that treatment with DMPS has some beneficial effects in experimental beryllium intoxication.

Animals↗
PubMed1995

The utility of chelating agents as antidotes for nephrotoxicity of gold sodium thiomalate in adjuvant-arthritic rats.

The effects of 2,3-dimercaptopropane sulphonate (DMPS) and N-(2-mercapto-2-methylpropanoyl)-L-cysteine (bucillamine) against the renal damage induced by gold sodium thiomalate (AuTM) in adjuvant-arthritic rats were studied. Arthritic rats induced by adjuvant using Mycobacterium butyricum were injected intraperitoneally with a chelating agent (0.6 mmol/kg) immediately after intramuscular injection of AuTM (0.066 mmol/kg) every other day for 21 days. Treatment with DMPS and bucillamine prevented increases in the urinary excretion of protein, aspartate aminotransferase, and glucose and blood urea nitrogen level after AuTM injection. AuTM prevented the increase in both adjuvant-injected and uninjected hind-feet volumes. The prevention of these inflamed lesions by AuTM was not affected by DMPS and bucillamine. These chelating agents decreased the gold concentration in the kidney and liver after AuTM administration, but did not affect the hepatic and renal concentrations of copper, zinc, iron, and calcium except the renal copper level after AuTM. These findings suggest that DMPS and bucillamine are very useful antidotes for gold toxicity.

Animals↗
PubMed1994

Protective effects of 2,3-dimercaptopropane-1-sulfonate on mercuric chloride-induced acute inhibition of enzymes from rat duodenal mucosa and kidney cortex.

Acute inhibitory effects of mercuric chloride on the activities of several enzymes from rat duodenal mucosa and kidney cortex and the protection provided by 2,3-dimercaptopropane-1-sulfonate (DMPS) were examined. Activities of carbonic anhydrase in homogenate, brush border and cytosol and of Mg(2+)-dependent, HCO3-stimulated ATPase in homogenate and brush border of duodenal mucosa and kidney cortex and activities of kidney microsomal Mg(2+)-dependent, Na(+)-K(+)-stimulated ATPase were all decreased following administration of HgCl2 (1-3 mg Hg/kg body weight s.c. once daily for 3 days). Decreases occurred generally in a dose-dependent manner and went back to near normal or normal levels by the combined administration of 20 and 30 mg DMPS/kg per day for 3 days. The concentration of serum urea nitrogen was increased about 8 times by the administration of 2 mg Hg/kg and restored to normal by the concomitant administration of 30 mg DMPS/kg. After the administration of 2 mg Hg/kg per day for 3 days, about half of the renal cortical proximal tubuli were necrotic. Administration of 30 mg DMPS/kg restored these changes to almost normal. The results suggest that DMPS is useful in mitigating acute Hg poisoning and that part of the protective effect of DMPS on enzyme damage induced by Hg poisoning may be due to its chelating action.

Animals↗
PubMed1995

Mobilization of heavy metals by newer, therapeutically useful chelating agents.

Four chelating agents that have been used most commonly for the treatment of humans intoxicated with lead, mercury, arsenic or other heavy metals and metalloids are reviewed as to their advantages, disadvantages, metabolism and specificity. Of these, CaNa2EDTA and dimercaprol (British anti-lewisite, BAL) are becoming outmoded and can be expected to be replaced by meso-2,3-dimercaptosuccinic acid (DMSA, succimer) for treatment of lead intoxication and by the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS, Dimaval) for treating lead, mercury or arsenic intoxication. Meso-2,3-DMSA and DMPS are biotransformed differently in humans. More than 90% of the DMSA excreted in the urine is found in the form of a mixed disulfide in which each of the sulfur atoms of DMSA is in disulfide linkage with an L-cysteine molecule. After DMPS administration, however, acyclic and cyclic disulfides of DMPS are found in the urine. The Dimaval-mercury challenge test holds great promise as a diagnostic test for mercury exposure, especially for low level mercurialism. Urinary mercury after Dimaval challenge may be a better biomarker of low level mercurialism than unchallenged urinary mercury excretion.

Animals↗