H. Vasken Aposhian's research while affiliated with The University of Arizona and other places
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Publications (144)
Background: Concerns for arsenic exposure are not limited to toxic waste sites and massive poisoning events. Chronic exposure continues to be a major public health problem worldwide, affecting hundreds of millions of persons.
Objectives: We reviewed recent information on worldwide concerns for arsenic exposures and public health to heighten awarene...
We determined the gastrointestinal absorption of the arsenic in Ironite, a readily available fertilizer, for male hamsters (Golden Syrian), considered to be an excellent model for how the human processes inorganic arsenic. Urine and feces were collected after administering an aqueous suspension of Ironite by stomach tube. In addition, we studied th...
Hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days and control hamsters were given tap water. Equal amounts of protein from the urinary bladder or liver extracts of control and arsenic-treated hamsters were labeled with Cy3 and Cy5 dyes, respectively. The labeled proteins were mixed and separated in the two-dimensio...
Inorganic arsenic is a human carcinogen to which millions of people are exposed via their naturally contaminated drinking water. Its molecular mechanisms of carcinogenicity have remained an enigma, perhaps because arsenate is biochemically transformed to at least five other arsenic-containing metabolites. In the biotransformation of inorganic arsen...
We have tried to address five questions dealing with five of the arms of arsenic toxicology: biotransformation, ROS, polymorphism, treatment, and protein binding. The first question, "What enzyme is responsible for the methylation of arsenic species in the human?", still needs further investigative effort to obtain an answer. The dilemma continues....
Human monomethylarsenate reductase [MMA(V) reductase] and human glutathione S-transferase omega 1-1 (hGSTO1-1) [because MMA(V) reductase and hGSTO1-1 are identical proteins, the authors will utilize the designation "hGSTO1-1"] are identical proteins that catalyze the reduction of arsenate, monomethylarsenate [MMA(V)], and dimethylarsenate [DMA(V)]....
This laboratory has studied the enzymology involved in the biotransformation of inorganic arsenic to dimethylarsinous acid (DMA(III)) and in human studies established that monomethylarsonous acid (MMA(III)) and DMA(III) appear in urine of people chronically exposed to arsenic. It appears that only two proteins are required for inorganic arsenic bio...
The aim of this review is to compare the metabolism, chemistry, and biological effects to determine if either of the industrial arsenicals (arsine and gallium arsenide) act like the environmental arsenic oxides (arsenite and arsenate). The metabolism of the arsenic oxides has been extensively investigated in the past 4 years and the differences bet...
The biotransformation of inorganic arsenate to dimethylarsinic acid (DMA) involves a series of enzymatic steps. Recent studies based on amino acid homology and other properties demonstrate that the human liver arsenate reductase and the human purine nucleoside phosphorylase (PNP) are identical proteins. The reaction requires inosine and dihydrolipo...
Arsenic compounds with a +3 oxidation state are more toxic than analogous compounds with a +5 oxidation state, for example, arsenite versus arsenate, monomethylarsonous acid (MMA(III)) versus monomethylarsonic acid (MMA(V)), and dimethylarsinous acid (DMA(III)) versus dimethylarsinic acid (DMA(V)). It is no longer believed that the methylation of a...
Large interindividual variability in urinary arsenic profiles, following chronic inorganic arsenic exposure, is well-known in humans. To understand this variability, we studied the relationship between polymorphisms in the gene for human monomethylarsonic acid (MMA(V)) reductase/hGSTO1 and the urinary arsenic profiles of individuals chronically exp...
Estimating the nature and extent of human cancer risks due to arsenic (As) in drinking water is currently of great concern, since millions of persons worldwide are exposed to arsenic, primarily through natural enrichment of drinking water drawn from deep wells. Humans metabolize and eliminate As through oxidative methylation and subsequent urinary...
A short and efficient synthesis of sodium dimethylarsinate-14C is described. Incorporation of the label has been achieved by methylation of methyldiiodo-arsine with iodomethane-14C. Product was precipitated and separated from sodium iodide by washing with acetone. Copyright © 2003 John Wiley & Sons, Ltd.
Some medical practitioners prescribe GSH and vitamin C alone or in combination with DMPS or DMSA for patients with mercury exposure that is primarily due to the mercury vapor emitted by dental amalgams.
This study tested the hypothesis that GSH, vitamin C, or lipoic acid alone or in combination with DMPS or DMSA would decrease brain mercury.
Young...
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(I...
Arsenic is an environmental hazard and the reduction of drinking water arsenic levels is under consideration. People are exposed to arsenic not only through drinking water but also through arsenic-contaminated air and food. Here we report the health effects of arsenic exposure from burning high arsenic-containing coal in Guizhou, China. Coal in thi...
An arsenate reductase has been partially purified from human liver using ion exchange, molecular exclusion, hydroxyapatite chromatography, preparative isoelectric focusing, and electrophoresis. When SDS-beta-mercaptoethanol-PAGE was performed on the most purified fraction, two bands were obtained. One of these bands was a 34 kDa protein. Each band...
Arsenic is an environmental hazard and the reduction of drinking water arsenic levels is under consideration. People are exposed to arsenic not only through drinking water but also through arsenic-contaminated air and food. Here we report the health effects of arsenic exposure from burning high arsenic-containing coal in Guizhou, China. Coal in thi...
Inorganic arsenic is an important environmental toxicant of both natural and anthropogenic sources. It is a human carcinogen for which appropriate animal models of most arsenic-induced cancers are missing. Although methylation of inorganic arsenic has been considered its primary mechanism for detoxification, the results of recent investigations dis...
The drinking of water containing large amounts of inorganic arsenic is a worldwide major public health problem because of arsenic carcinogenicity. Yet an understanding of the specific mechanism(s) of inorganic arsenic toxicity has been elusive. We have now partially purified the rate-limiting enzyme of inorganic arsenic metabolism, human liver MMA(...
Monomethylarsonous acid (MMA(III)), a metabolite of inorganic arsenic, has received very little attention from investigators of arsenic metabolism in humans. MMA(III), like sodium arsenite, contains arsenic in the +3 oxidation state. Although we have previously demonstrated that it is more toxic than arsenite in cultured Chang human hepatocytes, th...
The formation of monomethylarsonous acid (MMA(III)) by tissue homogenates of brain, bladder, spleen, liver, lung, heart, skin, kidney, or testis of male Golden Syrian hamsters was assessed using [(14)C]monomethylarsonic acid (MMA(V)) as the substrate for MMA(V) reductase. The mean +/- SEM of MMA(V) reductase specific activities (nanomoles of MMA(II...
In this study we report on the finding of monomethylarsonous acid [MMA(III)] in human urine. This newly identified arsenic species is a key intermediate in the metabolic pathway of arsenic biomethylation, which involves stepwise reduction of pentavalent to trivalent arsenic species followed by oxidative addition of a methyl group. Arsenic speciatio...
Biomethylation is the major human metabolic pathway for inorganic arsenic, and the speciation of arsenic metabolites is essential to a better understanding of arsenic metabolism and health effects. Here we describe a technique for the speciation of arsenic in human urine and demonstrate its application to the discovery of key arsenic metabolic inte...
In this study we report on the finding of monomethylarsonous acid [MMA(III)] in human urine. This newly identified arsenic species is a key intermediate in the metabolic pathway of arsenic biomethylation, which involves stepwise reduction of pentavalent to trivalent arsenic species followed by oxidative addition of a methyl group. Arsenic speciatio...
Mercuric chloride toxicity in mammals can be overcome by co-administration of sodium selenite. We report a study of the mutual detoxification product in rabbit plasma, and of a Hg−Se−S-containing species synthesized by addition of equimolar mercuric chloride and sodium selenite to aqueous, buffered glutathione. Chromatographic purification of this...
Monomethylarsonous acid (MMA(III)) has been detected for the first time in the urine of some humans exposed to inorganic arsenic in their drinking water. Our experiments have dealt with subjects in Romania who have been exposed to 2.8, 29, 84, or 161 microg of As/L in their drinking water. In the latter two groups, MMA(III) was 11 and 7% of the uri...
In order to confirm the solution structure of [(GS)2AsSe]− (GS = glutathione), we have investigated the retention behaviour of a [(GS)2AsSe]−/oxidized glutathione (GSSG) mixture on a Sephadex G-25 (SF) column with Tris buffers (0.1 mol dm−3, pH 8.0) containing various surfactants at concentrations above the critical micellar concentration (CMC): h...
The administration of sodium 2,3-dimercapto-1-propane sulfonate (DMPS) to humans chronically exposed to inorganic arsenic in their drinking water resulted in the increased urinary excretion of arsenic, the appearance and identification of monomethylarsonous acid (MMA(III)) in their urine, and a large decrease in the concentration and percentage of...
The administration of sodium 2,3-dimercapto-1-propane sulfonate (DMPS) to humans chronically exposed to inorganic arsenic in their drinking water resulted in the increased urinary excretion of arsenic, the appearance and identification of monomethylarsonous acid (MMAIII) in their urine, and a large decrease in the concentration and percentage of ur...
Among the most startling observations in mammalian toxicology is that a lethal dose of selenium can be overcome by an otherwise lethal dose of arsenic. We report the molecular basis of this antagonism. Using X-ray absorption spectroscopy we have identified a new arsenic−selenium compound in the bile of rabbits injected with aqueous selenite and ars...
Methylation has been considered to be the primary detoxication pathway of inorganic arsenic. Inorganic arsenic is methylated by many, but not all animal species, to monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)), and dimethylarsinic acid (DMA(V)). The As(V) derivatives have been assumed to produce low toxicity, but the relative...
An arsenate (As(V)) reductase has been partially purified from human liver. Its apparent molecular mass is approximately 72 kDa. The enzyme required a thiol and a heat stable cofactor for activity. The cofactor is less than 3 kDa in size. The thiol requirement can be satisfied by dithiothreitol (DTT). However, the extent of stimulation of reductase...
A unique enzyme, MMA(V) reductase, has been partially purified from rabbit liver by using DEAE-cellulose, carboxymethylcellulose, and red dye ligand chromatography. The enzyme is unique since it is the rate-limiting enzyme in the biotransformation of inorganic arsenite in rabbit liver. The K(m) and V(max) values were 2.16 x 10(-)(3) M and 10.3 micr...
Arsenate is reduced to arsenite enzymatically by arsenate reductase and nonenzymatically by GSH. An early step in the detoxification appears to be the formation of the Gailer compound, seleno-bis(S-glutathionyl) arsinium ion, which is rapidly formed and excreted in the bile. Arsenite-binding proteins initially may prevent or enhance the accumulatio...
A meeting on the health effects of arsenic (As), its modes of action, and areas in need of future research was held in Hunt Valley, Maryland, on 22-24 September 1997. Exposure to As in drinking water has been associated with the development of skin and internal cancers and noncarcinogenic effects such as diabetes, peripheral neuropathy, and cardiov...
Inorganic arsenite is methylated by some, but not all, animal species to dimethylarsinic acid (DMA). The monomethyl compound containing arsenic in an oxidation state of +3 has been proposed as an intermediate. Using highly purified arsenic methyltransferase from rabbit liver and the partially purified enzyme from Chang human liver hepatocytes, the...
Biotransformation of inorganic arsenic in mammals is catalyzed by three serial enzyme activities: arsenate reductase, arsenite methyltransferase, and monomethylarsonate methyltransferase. Our laboratory has purified and characterized these enzymes in order to understand the mechanisms and elucidate the variations of the responses to arsenate/arseni...
Inorganic arsenic is considered a high-priority hazard, particularly because of its potential to be a human carcinogen. In exposed human populations, arsenic is associated with tumors of the lung, skin, bladder, and liver. While it is known to be a human carcinogen, carcinogenesis in laboratory animals by this metalloid has never been convincingly...
Although inorganic arsenic is methylated enzymatically by arsenic methyltransferases, which have been found in many mammalian livers, the detection of such enzymes has not been successful in surgically removed human livers. Results of the present experiments demonstrated that methylvitamin B12 (methylcobalamin, CH3B12) in the presence of thiols and...
Manganese concentrates in the ventral mesencephalon of male Sprague-Dawley rats after intrathecal administration of MnCl2. We tested the hypothesis that Mn concentration in the central nervous system (CNS), particularly in the ventral mesencephalon, is decreased by inhibiting dopamine reuptake using cocaine or by decreasing dopamine concentrations...
DMPS (2,3-dimercaptopropane-1-sulfonate, Na salt), when used as a challenge test for mercury in workers involved in the production of a calomel skin-bleaching lotion and in direct contact with mercurous chloride, elevated urine levels of mercury. A DMPS treatment regimen was devised and initiated. Three days after the challenge test, DMPS was admin...
Methylation of inorganic arsenic to methylarsonic acid (MMA) and dimethylarsinic acid (DMA) has been considered to be the major pathway of inorganic arsenic biotransformation and detoxification. Comparative studies, in vivo, have demonstrated variation in the abilities of animals to methylate inorganic arsenic. We propose that the rate of inorganic...
Sodium 2,3-dimercapto-1-propane sulfonate (DMPS, Dimaval) is a water-soluble chelating agent that can be given by mouth or systemically and has been used to treat metal intoxication since the 1960s in the former Soviet Union and since 1978 in Germany. To better approximate the body burdens of Hg and As in humans, DMPS-Hg andDMPS-As challenge tests...
Potential toxicity from exposure to mercury vapor (Hg(o)) from dental amalgam fillings is the subject of current public health debate in many countries. We evaluated potential central nervous system (CNS) toxicity associated with handling Hg-containing amalgam materials among dental personnel with very low levels of Hg(o) exposure (i.e., urinary Hg...
A Across-study design was used to evaluate the sensitivities of five psychomotor tasks previously used to assess preclinical effects of low-level Hg0 (urinary < or =55 microg/l). Pooling dental professional subject populations from six studies conducted over the last 6 years, a larger study population was obtained with a high degree of uniformity (...
With the development of a rapid assay for arsenite methyltransferase (Zakharyan et al., 1995), the specific activity of this critical enzyme for arsenite biotransformation was determined by incubating liver, testis, kidney, or lung cytosol of male B6C3F1 mice with sodium arsenite and S-[methyl-3H]adenosyl-L-methionine and measuring the formation of...
The purpose of the present study was to evaluate in a novel manner the arsenic exposure of humans living in two towns in Northeastern Chile. Residents of one town drink water containing 593 microg As/l. Those in the control town drink water containing 21 microg As/l. Our hypothesis was that the administration of the chelating agent, 2,3-dimercaptop...
Using an in vitro assay which measures the transfer of a radiolabeled methyl moiety of S-[methyl-3H]adenosylmethionine ([3H]SAM) to arsenite or monomethylarsonate (MMA) to yield [methyl-3H]MMA or [methyl-3H]dimethylarsinate (DMA) respectively, guinea pig liver cytosol was found to be deficient in the enzyme activities which methylate these substrat...
Arsenic metabolism has typically been studied by administering arsenate or arsenite into animals and humans and then studying the metabolites excreted in the urine. Although such studies have yielded information about the beginning and the end of the metabolic pathways for the metabolism of inorganic arsenic compounds, any statements as to the mole...
Mercury is an environmental contaminant that preferentially accumulates in the kidney. It has been previously shown using proton-induced X-ray emission analysis that mercury (HgCl2) accumulated in precision-cut rabbit renal cortical slices. In this study, the efficacy of seven chelating agents for the removal of Hg from renal slices has been examin...
With the ever-increasing public health problems associated with inorganic arsenic (Chappell et al, 1994), there has been renewed interest in understanding the metabolism and toxicity of the compounds of this metalloid which has been shrouded with the mystique of homicides, suicides, illness, medicinal uses and even the fountain of youth. The Borgia...
The methylation of inorganic arsenic to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) have been generally considered to be the major pathway for inorganic arsenic biotransformation and detoxification. Yet, when arsenate/arsenite is injected into the Callithrix jacchus (marmoset) monkey or chimpanzee, monomethylarsonic acid and dimethy...
The sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (Dimaval; DMPS) challenge test has been given previously to humans exposed to elemental mercury (vapor) or mercuric salts, but not mercurous salts. The test (300 mg p.o., after an 11-hr fast) was given to 11 factory workers who make a skin lotion that contains mercurous chloride, eight users...
Since there has been concern about whether any of the chelating agents used therapeutically might cause an initial redistribution of heavy metals to the brain and since the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (Dimaval, DMPS) has been used to treat heavy metal intoxication in humans, the hypothesis that DMPS does not redistribute an...
The binding of 2,3-dimercapto-1-propanesulfonate (DMPS) in plasma was determined in three healthy young adults after a single 300-mg p.o. dose. By 5 hr after DMPS administration, 62.5% of the total plasma DMPS was bound to proteins. The remainder consisted of nonprotein associated DMPS disulfides (36.6%) and unaltered DMPS (0.9%). Protein-bound DMP...
A rapid, accurate, in vitro assay utilizing radioactive S-adenosylmethionine (SAM) has been developed for the methylation of arsenite and monomethylarsonate (MMA) by rabbit liver methyltransferases. The assay has been validated by separating, identifying, and measuring the products of the reaction using chloroform extraction, ion exchange chromatog...
The intrathecal administration of MnCl2 to young male rats caused dopamine depletion in the caudate-putamen and a decrease in spontaneous motor activity. Our experiments demonstrate that in the young rat: (a) the lateral choroid plexus protects the cerebrospinal fluid (CSF) from high concentrations of Mn in the blood by sequestering and thus preven...
The intrathecal administration of MnCl2 to young male rats caused doparnine depletion in the caudate-putamen and a decrease in spontaneous motor activity. Our experiments
demonstrate that in the young rat: (a) the lateral choroid plexus protects the cerebrospinal fluid (CSF) from high concentrations
of Mn in the blood by sequestering and thus preve...
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...
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...
It is well known that arsenite/arsenate (As3+/As5+) administered to rabbits is bound initially to cellular proteins of the liver before methylated arsenic metabolites appear in urine. This protein binding may decrease the in situ toxicity of inorganic arsenic by decreasing its metabolic availability until it is methylated enzymatically. We have inv...
We compared the pharmacokinetics of meso-2,3-dimercaptosuccinic acid (DMSA) in three children with lead poisoning, three adults with lead poisoning, and five healthy adult volunteers. All subjects received DMSA orally. Maximum blood concentration and time to maximum blood concentration of total DMSA concentration were not statistically different am...
The pharmacokinetics of 2,3-dimercaptopropane-1-sulfonate (DMPS), an effective chelating agent for mercury, were determined in five healthy adults after i.v. administration of 3.0 mg/kg of DMPS. DMPS is rapidly transformed to disulfide forms; 15 min after administration, only 12% of the total DMPS detected in blood was present as the parent drug. D...
Meso-2,3-dimercaptosuccinic acid (DMSA) in humans is an effective p.o. therapeutically useful chelating agent of Pb. In humans given DMSA p.o., the major urinary metabolite is DMSA-cysteine (1:2) mixed disulfide. In order to determine its efficacy in mobilizing Pb and increasing urinary Pb excretion, the mixed disulfide was given to rats treated pr...
meso-2,3-Dimercaptosuccinic acid is an orally active chelating agent useful for the treatment of lead intoxication. Since it is believed to be extracellular in its distribution, analogs have been synthesized in a search for one that will enter the cell and successfully compete for firmly bound intracellular toxic heavy metals such as cadmium and pl...
There is considerable controversy as to whether dental amalgams may cause systemic health effects in humans because they liberate elemental mercury. Most such amalgams contain as much as 50% metallic mercury. To determine the influence of dental amalgams on the mercury body burden of humans, we have given volunteers, with and without amalgams in th...
Meso-2,3-dimercaptosuccinic acid (DMSA) is bound to plasma albumin in humans and appears to be excreted in the urine as the DMSA-cysteine mixed disulfide. The pharmacokinetics of DMSA have been determined after its administration to humans po. For the blood, the tmax and t1/2 were 3.0 h + 0.45 SE and 3.2 h + 0.56 SE, respectively. The Cmax was 26.2...
Heavy metals cause irreversible neurobehavioral damage in many developing mammals, but the mechanisms of this damage are unknown. The influence of three heavy metal compounds, triethyllead chloride, lead acetate and cadmium chloride, on lethality, development, behavior and learning was studied using the fruit fly, Drosophila melanogaster. This anim...
The sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS) is used p.o. for the treatment of chronic lead and Hg intoxication in humans. The metabolism and pharmacokinetics of DMPS were determined after p.o. administration of 300 mg of DMPS to each of 10 normal young men. The absorbed DMPS was metabolized rapidly and extensively to a disulfide...
The ion association complex formed with the cadmium chelate of the dimethyl ester of meso-2,3-dimercaptosuccinic acid and the tetramethylammonium cation, [(Me)4N]2[Cd(DiMeDMSA)2], has been synthesized. The structures of the ion association complex and of the ligand (meso-DiMeDMSA) were determined by single-crystal X-ray diffraction. The two methyl...
The ion association complex formed with the cadmium chelate of the dimethyl ester of meso-2,3-dimercaptosuccinic acid and the tetramethylammonium cation, [(Me)4N]2[Cd(Di-MeDMSA)2], has been synthesized. The structures of the ion association complex and of the ligand (meso-DiMeDMSA) were determined by single-crystal X-ray diffraction. The two methyl...
The interactions of 210Po at the molecular level in biological systems have received little study even though this alpha-emitting radionuclide occurs widely in nature. Polonium-210 was given subcutaneously to rats and found to be incorporated into liver metallothionein as judged by a number of criteria including heat stability, acetone precipitatio...
Although heavy metal ions are known to be toxic to the central nervous system (CNS), the mechanisms by which the CNS may protect itself from initial challenges of such toxic ions is unknown. The choroid plexus is the principal site of formation of the cerebrospinal fluid (CSF) which bathes the brain. We have determined in rats and rabbits that afte...
The monomethyl ester of meso-dimercaptosuccinic acid (MoMeDMSA) and its chelates with lead(II), cadmium(II), and mercury(II) have been synthesized. The mercury(II) chelate of MoMeDMSA is formed by the coordination of the two sulfur atoms in MoMeDMSA, whereas the lead(II) and cadmium(II) chelates are formed by the coordination of one sulfur and one...
meso-2,3-Dimercaptosuccinic acid (DMSA) is orally effective for the treatment of chronic lead intoxication in humans. Earlier studies have shown that the majority of DMSA, given p.o. to normal humans, is excreted in the urine as mixed disulfides with L-cysteine. We have developed an assay for the determination of DMSA that has made possible the det...
Polonium-210 is one of the most hazardous radionuclides. As recently as 1988, there have been concerns regarding accidental exposures of humans to it. Yet, there have been no studies on the effectiveness of the newer dithiol chelating agents in increasing the excretion of this radioactive heavy metal. In order to accomplish this, a safe and effecti...
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...
The primary purpose of this article is to summarize the recent investigations dealing with the pharmacology and toxicology of meso-2,3-dimercaptosuccinic acid, an orally effective chelating agent. The need for a better chelating agent for treating young children and pregnant women with lead intoxication has been apparent for some time. Preclinical...
Polonium-210 is one of the most hazardous radionuclides. As recently as 1988, there have been concerns regarding accidental exposures of humans to it. Yet, there have been no studies on the effectiveness of the newer dithiol chelating agents in increasing the excretion of this radioactive heavy metal. In order to accomplish this, a safe and effecti...
Lead chelates of racemic- and meso-dimercaptosuccinic acid (DMSA) were synthesized and isolated from aqueous solutions and characterized by potentiometric measurements and infrared spectroscopy. Two types of lead chelates of racemic DMSA were isolated: one in which racemic-DMSA is coordinated to Pb+2 via one oxygen and one sulfur atom and the other...
There have been a number of new and exciting advances in the understanding of arsenic toxicity. Organic trivalent arsenicals have been the drug of choice in the treatment of African trypanosomes, the cause of sleeping sickness. In the past, various mechanisms have been proposed for their mode of action in the treatment of this parasitic disease. It...
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...
The urinary excretion of meso-2,3-dimercaptosuccinic acid (DMSA), which is an effective chelating agent for lead, was determined after the oral administration of 10 mg DMSA/kg to six normal young men. The DMSA that was absorbed was extensively biotransformed. After 14 hours only 2.53% of the administered DMSA was excreted in the urine as unaltered...
The water-soluble dithiol chelating agents meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS) are becoming of increasing importance for the treatment of lead, arsenic and mercury poisoning. There is, however, a paucity of data about their metabolic transformation. Male rabbits were given DMSA (0.20 mmol/kg) i.m...
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 biotran...
Virtually nothing is known about the biotransformation of the heavy metal chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA). Two fasted, normal, young men wera 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 biotran...
Disulfide metabolites of 2,3-dimercaptopropane-1-sulfonic acid (DMPS), a heavy metal chelating agent, have been found in the urine of catheterized rabbits after a single dose of DMPS. After treating the urine with a reducing agent such as NaBH4, a 20-fold increase in DMPS was observed within 6 hr after administration. This suggested the presence of...
Polonium-210 exposures, although rare, have occurred due to accidents in nuclear working environments. This alpha emitting radioactive element can bind thiols and thiol-containing proteins in vivo. Since thiol-containing chelating agents compete with many thiols for heavy metals, a number of these chelating agents have been investigated as protecti...
The presence of oxidized species of the dithiol-chelating agents, meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS), in human urine was determined by chemical and electrolytic reduction methods. Urine from a human given either DMSA or DMPS was treated with electrolysis, dithiothreitol, or sodium tetrahydridobo...
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 br...
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...
The ip LD50s of N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA) and British Anti-Lewisite (BAL) were 0.819 and 1.48 mmol/kg, respectively, in male albino mice. The ip ED50 of DMPA and BAL for prevention of the lethal effects of 0.15 mmol NaAsO2/kg was 0.022 and 0.169 mmol/kg, respectively. DMPA increased the LD50 of sodium arsenite by approximatel...
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...
Citations
... MAs(III), the initial product in the ArsM catalytic cycle has been proposed to have been an primordial antibiotic before the great oxygenation event (GOE; Chen and Rosen, 2020). After the GOE, MAs(III) would have been oxidized to methylarsenate (MAs(V)), essentially detoxifying it