R M Maiorino

The University of Arizona, Tucson, Arizona, United States

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Publications (33)98.99 Total impact

  • Pharmacology &amp Toxicology 03/2009; 59(s7):467 - 470.
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    ABSTRACT: 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 rats were exposed to elemental mercury by individual nose cone, at the rate of 4.0 mg mercury per m3 air for 2 h per day for 7 consecutive days. After a 7-day equilibrium period, DMPS, DMSA, GSH, vitamin C, lipoic acid alone, or in combination was administered for 7 days and the brain and kidneys of the animals removed and analyzed for mercury by cold vapor atomic absorption. None of these regimens reduced the mercury content of the brain. Although DMPS or DMSA was effective in reducing kidney mercury concentrations, GSH, vitamin C, lipoic acid alone, or in combination were not. One must conclude that the palliative effect, if any, of GSH, vitamin C, or lipoic acid for treatment of mercury toxicity due to mercury vapor exposure does not involve mercury mobilization from the brain and kidney.
    Journal of toxicology. Clinical toxicology 02/2003; 41(4):339-47.
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    ABSTRACT: 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 urinary arsenic while the monomethylarsonic acid (MMA(V)) was 14 and 13%, respectively. Of our 58 subjects, 17% had MMA(III) in their urine. MMA(III) was not found in urine of any members of the group with the lowest level of As exposure. If the lowest-level As exposure group is excluded, 23% of our subjects had MMA(III) in their urine. Our results indicate that (a) future studies concerning urinary arsenic profiles of arsenic-exposed humans must determine MMA(III) concentrations, (b) previous studies of urinary profiles dealing with humans exposed to arsenic need to be re-examined and re-evaluated, and (c) since MMA(III) is more toxic than inorganic arsenite, a re-examination is needed of the two hypotheses which hold that methylation is a detoxication process for inorganic arsenite and that inorganic arsenite is the major cause of the toxicity and carcinogenicity of inorganic arsenic.
    Chemical Research in Toxicology 09/2000; 13(8):693-7. · 3.67 Impact Factor
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    ABSTRACT: 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 urinary dimethylarsinic acid (DMA). This is the first time that MMA(III) has been detected in the urine. In vitro biochemical experiments were then designed and performed to understand the urinary appearance of MMA(III) and decrease of DMA. The DMPS-MMA(III) complex was not active as a substrate for the MMA(III) methyltransferase. The experimental results support the hypothesis that DMPS competes with endogenous ligands for MMA(III), forming a DMPS-MMA complex that is readily excreted in the urine and points out the need for studying the biochemical toxicology of MMA(III). It should be emphasized that MMA(III) was excreted in the urine only after DMPS administration. The results of these studies raise many questions about the potential central role of MMA(III) in the toxicity of inorganic arsenic and to the potential involvement of MMA(III) in the little-understood etiology of hyperkeratosis, hyperpigmentation, and cancer that can result from chronic inorganic arsenic exposure.
    Toxicology and Applied Pharmacology 06/2000; 165(1):74-83. · 3.98 Impact Factor
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    ABSTRACT: 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 of the skin lotion and nine controls. Urines were analyzed for total mercury by using cold vapor atomic absorption spectrophotometry. The mercury excreted for 6 hr before and 6 hr after DMPS treatment was 113 micrograms +/- 26 and 5037 micrograms +/- 682 S.E.M. for the skin lotion makers; 16.2 micrograms +/- 3.4 and 1410 micrograms +/- 346 S.E.M. for the skin lotions users; and 0.49 micrograms +/- 0.11 and 18.4 micrograms +/- 7.1 S.E.M. for the controls, respectively. The increases in urinary mercury resulting from the DMPS challenge test were 45-, 87- and 38-fold, respectively. The results demonstrate that, in humans exposed to mercurous chloride, DMPS increases the urinary excretion of mercury and that the DMPS/mercury challenge test is of value for a more realistic estimation of mobilizable mercury. An attempt to associate genotoxicity, as indicated by micronuclei content in buccal cells, with mercury exposure was inconclusive, perhaps because of the small number of subjects.
    Journal of Pharmacology and Experimental Therapeutics 06/1996; 277(2):938-44. · 3.89 Impact Factor
  • M M Aposhian, R M Maiorino, Z Xu, H V Aposhian
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    ABSTRACT: 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 and increase lead or mercuric ions in the brains of rats was tested. Lead acetate at a concentration of 50 mg/l was made available in the drinking water of rats for 86 days. Other rats received intraperitoneal injections of 0.50 mg Hg/kg (as mercuric chloride) each day for 5 days a week for a total of 32 or 41 days. Animals were divided into groups and given, i.p., either 0.27 mmol DMPS/kg body weight or saline, each day for 1, 2, 3 or 4 days. Lead or mercury concentrations of the brain were determined after each group received DMPS for the different number of days. DMPS treatment did not result in any initial increase of lead or mercuric ions in the brain. The mercury content of the kidney decreased. The results of these experiments demonstrated that lead or mercuric ions were not redistributed to or increased in the brains of rats during the initial days of DMPS treatment.
    Toxicology 06/1996; 109(1):49-55. · 4.02 Impact Factor
  • R M Maiorino, Z F Xu, H V Aposhian
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    ABSTRACT: 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 DMPS consisted of a DMPS-albumin complex (84%) and a higher molecular weight protein complex (16%), perhaps albumin aggregates. DMPS was released from the isolated DMPS-albumin complex after treatment with dithiothreitol, indicating that it was bound via a disulfide linkage. The half-life of unaltered DMPS was 1.8 hr, whereas that of altered DMPS was 20 hr, suggesting that the DMPS-albumin disulfide complex is stable and that DMPS was released from it slowly. In addition, the biotransformation of OMPS to disulfide forms was extensive. By 9 hr after administration, 10% of the total urinary DMPS was unchanged drug and 90% was altered DMPS. The latter was converted to DMPS by dithiothreitol, indicating that the altered DMPS consisted of disulfides. In 2- to 4-hr urine, DMPS disulfides included cyclic polymeric DMPS disulfides (97%), DMPS-cysteine (1:2) mixed disulfide (2.5%) and acyclic DMPS disulfide (0.5%). The cyclic polymeric DMPS disulfides were present in a major (91.5%) and minor (5.5%) form. DMPS-albumin mixed disulfide and nonprotein DMPS disulfides may prolong the heavy metal mobilizing activity of DMPS and thus may represent reservoirs of DMPS which can be released by disulfide reduction in vivo.
    Journal of Pharmacology and Experimental Therapeutics 05/1996; 277(1):375-84. · 3.89 Impact Factor
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    ABSTRACT: 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.
    Toxicology 04/1995; 97(1-3):23-38. · 4.02 Impact Factor
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    ABSTRACT: The sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS) challenge test (300 mg p.o. after an 11-hr fast) was given in Monterrey, Mexico to dental and nondental personnel. Urine samples were collected and analyzed for total mercury. The mean mercury urinary excretion (+/- S.E.) for 6 hr before and 6 hr after DMPS administration for 10 dental technicians, who formulate amalgam, was 4.84 micrograms +/- 0.742 and 424.0 micrograms +/- 84.9; for 5 dentists, who use amalgam in their practice, 3.28 micrograms +/- 1.11 and 162.0 micrograms +/- 51.2; and for 13 nondental personnel, 0.783 microgram +/- 0.189 and 27.3 micrograms +/- 3.19. The urinary coproporphyrin levels before DMPS administration, which are indicative of renal mercury content, were quantitatively associated with the urinary mercury levels among the three study groups after DMPS administration. This was not so if the urinary mercury level before DMPS administration was compared with the urinary coproporphyrin concentration. The urinary mercury level after DMPS administration is a better indicator of exposure and renal mercury burden than is the mercury level measured in the urine before DMPS is given. Regression analysis showed that the coefficient of urinary mercury was statistically and adversely associated with complex attention (switching task), the perceptual motor task (symbol-digit substitution), symptoms and mood. The easily performed DMPS-mercury challenge test is useful for monitoring dental personnel for mercury vapor exposure.
    Journal of Pharmacology and Experimental Therapeutics 02/1995; 272(1):264-74. · 3.89 Impact Factor
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    ABSTRACT: 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, DimavalR) 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 disulflde 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.
    Toxicology. 01/1995;
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    ABSTRACT: 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 among the groups. Unaltered DMSA was detected in the blood of all poisoned patients but in only one of five healthy volunteers. Elimination half-life of total DMSA (parent drug plus oxidized metabolites) was longer in children with lead poisoning (3.0 +/- 0.2 hours) than in adults with lead poisoning (1.9 +/- 0.4 hours) and healthy adults (2.0 +/- 0.2 hours). Renal clearance of total DMSA was greater in healthy adults (77.0 +/- 13.2 ml/min per square meter) than in either adults (24.7 +/- 3.3 ml/min per square meter) or children with lead poisoning (16.6 ml/min per square meter); renal clearance of the metabolites of DMSA was also greater in healthy adults (64.6 +/- 10.1 ml/min per square meter) than in either adults (35.4 +/- 8.4 ml/min per square meter) or children with lead poisoning (19.5 ml/min per square meter). The DMSA appeared to enter the erythrocytes of patients with lead poisoning to a greater extent than in healthy adults. We conclude that renal clearance of DMSA and its metabolites may be impaired and that the distribution of DMSA in children with lead poisoning may be different from that in adults.
    Journal of Pediatrics 09/1994; 125(2):309-16. · 4.04 Impact Factor
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    ABSTRACT: 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. DMPS and its metabolites were eliminated primarily by the kidneys. By 96 hr after administration, 12% of the total DMPS found in the urine was excreted as the parent drug (10% of the administered dose) and 88% was excreted as disulfide metabolites (74% of the administered dose). The disposition of parent drug was described by a biexponential equation with an elimination half-life of 1.8 hr. By contrast, the elimination half-life of total DMPS was 20 hr. The oral bioavailability of the parent drug was found in a separate study to be 39%. Mercury excretion in healthy volunteers correlated well with the urinary excretion of both the parent drug (r2 = .94) and the disulfide metabolites (r2 = .96).
    Journal of Pharmacology and Experimental Therapeutics 03/1994; 268(2):662-8. · 3.89 Impact Factor
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    ABSTRACT: 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 previously with Pb acetate. The mixed disulfide was as effective as DMSA in increasing the urinary excretion of Pb and mobilizing Pb from the kidney. DMSA, however, appears to be superior for mobilizing Pb from the liver and the brain. After the mixed disulfide was given s.c. to rats, DMSA was found in the blood and urine. Twenty-four hours after administration, 0.7% of the administered mixed disulfide was found in the urine as DMSA, indicating the mixed disulfide can be reduced to DMSA. The mixed disulfide was also reduced in vitro to DMSA during incubation with rat blood. Although in the rat the DMSA-cysteine (1:2) mixed disulfide mobilized Pb from the kidney, increased the urinary excretion of Pb and was to some extent reduced to DMSA, its fate and pharmacological properties in the human, where it is found after DMSA administration, are unknown.
    Journal of Pharmacology and Experimental Therapeutics 01/1994; 267(3):1221-6. · 3.89 Impact Factor
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    ABSTRACT: 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 microM + 4.7 SE. To determine whether dental amalgams influence the human body burden of mercury, we gave volunteers the sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS). The diameters of dental amalgams of the subjects were determined to obtain the amalgam score. Administration of 300 mg DMPS by mouth increased the mean urinary mercury excretion of subjects over a 9 h period. There was a positive correlation between the amount of mercury excreted and the amalgam score. DMPS might be useful for increasing the urinary excretion of mercury and thus increasing the significance and reliability of this measure of mercury exposure. DMSA analogs have been designed and synthesized in attempts to increase the uptake by cell membranes of the DMSA prototype chelating agents. The i.v. administration of the monomethyl ester of DMSA, the dimethyl ester of DMSA or the zinc chelate of dimethyl DMSA increases the biliary excretion of platinum and cadmium in rats.
    Journal of toxicology. Clinical toxicology 02/1992; 30(4):505-28.
  • R M Maiorino, R C Dart, D E Carter, H V Aposhian
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    ABSTRACT: 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 form(s). By 24 hr after DMPS administration, the area under the blood concentration-time curve of unaltered DMPS was 3.9 compared to 143 for altered DMPS. Altered DMPS is the difference between total DMPS and unaltered DMPS. Unaltered DMPS is the unbound, parent compound;, total DMPS consists of unaltered DMPS plus oxidized [disulfide] DMPS which is determined after reduction with dithiothreitol. In blood the altered form was confined to plasma. By 15 hr, only 3.7% of the administered DMPS was excreted in the urine as unaltered DMPS and 38.7% as altered DMPS. The unaltered and altered DMPS represented 9 and 91%, respectively, of the total amount of DMPS in the urine. Altered DMPS was converted to unaltered DMPS by treatment with dithiothreitol, which indicates that the altered DMPS is a disulfide(s). There was a high correlation between the urinary excretion of Hg and the urinary excretion of unaltered DMPS (r = 0.920 +/- 0.022 S.E.).
    Journal of Pharmacology and Experimental Therapeutics 12/1991; 259(2):808-14. · 3.89 Impact Factor
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    ABSTRACT: 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 determination of the form of DMSA in blood and plasma. After p.o. administration of 10 mg DMSA/kg to four normal young men, no unaltered DMSA (unaltered DMSA is the unbound, parent compound; total DMSA consists of unaltered DMSA plus oxidized (disulfide) DMSA and is determined after reduction with dithiothreitol) was found in the blood over an 8-hr period. Only after treatment of blood or plasma with the disulfide-reducing agent, dithiothreitol, was DMSA detected. This indicates that DMSA is in disulfide linkage with plasma proteins and/or non-protein sulfhydryl compounds. Most of the DMSA in the plasma (92-95%) was found to be bound to plasma proteins, mainly albumin. The remaining DMSA may be bound to small molecular weight (less than 10,000 MW) nonprotein sulfhydryl compounds such as cysteine. Plasma protein appears to serve as a depot and reservoir of DMSA, which can exchange for cysteine. The urinary excretion of unaltered DMSA and DMSA mixed disulfides with L-cysteine suggests that this exchange takes place at the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
    Journal of Pharmacology and Experimental Therapeutics 09/1990; 254(2):570-7. · 3.89 Impact Factor
  • W Zheng, R M Maiorino, K Brendel, H V Aposhian
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    ABSTRACT: 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.
    Fundamental and Applied Toxicology 05/1990; 14(3):598-607.
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    H V Aposhian, R M Maiorino, R C Dart, D F Perry
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    ABSTRACT: 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 DMSA and 18.1% as altered forms. The unaltered DMSA was 12% of the total DMSA found in the urine. The altered form(s) of DMSA was 88% of the total urinary DMSA. The altered DMSA can be converted to unaltered DMSA by electrolytic reduction, which indicates that the altered forms of DMSA are disulfides. The excretion of altered DMSA reached a peak between 2 and 4 hours after DMSA administration. There were small but statistically significant increases in the excretion of zinc, copper, and lead after DMSA administration. DMSA did not influence the urinary excretion of 27 other metals and elements.
    Clinical Pharmacology &#38 Therapeutics 06/1989; 45(5):520-6. · 6.85 Impact Factor
  • R M Maiorino, H V Aposhian
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    ABSTRACT: 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., and urine was collected over a 6-hr period. Monobromobimane derivatization, HPLC separation, and fluorescence detection, along with [U-14C]DMSA data, demonstrated that the total 14C found in the urine was distributed as 73% unaltered DMSA, 7% mercaptosuccinic acid and 6 and 14% of two unknowns. Electrolytic reductive treatment of the urine did not increase the urinary content of DMSA, indicating that oxidative biotransformation is not a major pathway for DMSA in the rabbit. This latter result is strikingly different from that for DMPS in rabbit.
    Biochemical Pharmacology 05/1989; 38(7):1147-54. · 4.58 Impact Factor
  • R M Maiorino, D C Bruce, H V Aposhian
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    ABSTRACT: 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.
    Toxicology and Applied Pharmacology 03/1989; 97(2):338-49. · 3.98 Impact Factor