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

doi:10.1016/0300-483X(94)02903-8

Toxicology

Volume 95, Issues 1–3, 6 January 1995, Pages 167-175

https://doi.org/10.1016/0300-483X(94)02903-8 Get rights and content

Abstract

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.

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Cited by (21)

Chelation Treatment During Acute and Chronic Metal Overexposures-Experimental and Clinical Studies
2016, Chelation Therapy in the Treatment of Metal Intoxication
Metal overexposures, ranging from nonsymptomatic, elevated body levels to life threatening acute or chronic poisonings, should in general be treated by eliminating the exposure source, by various decontamination procedures, and by supportive treatment. However, in a quite extensive number of cases, various chelation treatment schedules offer an efficient way of handling the adverse effects of overexposure to metals, either by reducing the toxicity of the metal by forming a less toxic complex, by changing the toxicodynamics of the metal thereby reducing the interaction of the metal with a vulnerable target, and/or reducing its uptake and/or enhancing its excretion.
The present chapter offers a systematic review of the present state-of-the-art for chelation treatment of metal overexposures. Such exposures can be due to occupational, environmental, dietary, or lifestyle factors, or iatrogenic procedures. The review is ordered alphabetically citing animal experimental studies and epidemiological and clinical studies for each metal, if available.
The general experience is that the metal (Lewis acid) and the chelator (Lewis base) should have high affinity for each other (high stability constant), thus soft metals should be chelated by chelators with soft ligands (eg, C-SH), and hard metals with chelators with hard ligands (eg, COOH, CRO, CR2OH). Intermediate metals prefer, for example, N-containing ligands, but can be chelated by both hard and soft bases. However, the pharmacokinetics of the chelating agent is highly important also, especially whether the chelator and the metal-chelator complex formed are hydrophilic with enhanced renal excretion as result, or lipophilic with enhanced biliary excretion and/or brain deposition as a potential result.
Some important questions are: Can the chelator be administered orally, and will it enhance or prevent systemic uptake of toxic metal remaining in the gastrointestinal tract? Is the chelator metabolically stable to allow extended treatment with appropriate time lag between doses?
According to generally accepted ethical principles in pharmacology and medicine, experimental chelating agents proven efficient in animal experiments cannot be used in humans except in special cases, where the benefit clearly outweighs the potential toxicity of the agent. Based on the experimental and clinical work, optimal chelating agents for acute poisonings with selected metals are as follows:
Deferoxamine for aluminum compounds.
Dimercaptosulfonate (DMPS) for arsenic compounds, deferoxamine for iron compounds, with deferiprone and deferasirox as potential alternative chelators.
Dimercaptosuccinic acid (DMSA) for lead compounds, DMPS for inorganic mercury compounds including mercury vapor, DMSA may be superior for organic mercury compounds.
Today new chelators are being developed as decorporating agents for all classes of metals.
Complexes of beryllium(II) with substituted malonates. Crystal structure of K<inf>2</inf>[Be(C<inf>4</inf>H<inf>6</inf>(COO)<inf>2</inf>) <inf>2</inf>]·2H<inf>2</inf>O
1999, Polyhedron
The complexes formed by beryllium(II) with the dicarboxylate ligands methylmalonate, phenylmalonate, dimethylmalonate and cyclobutane-1,1-dicarboxylate have been investigated in aqueous solution through potentiometric and ⁹Be NMR spectroscopic measurements. The species BeL, [BeL₂]²⁻, [Be₃(OH)₃L₃]³⁻ and [Be₃(OH)₃L]⁺ have been identified and their formation constants have been determined at 25°C in 0.5 mol dm⁻³ NaClO₄. The stability of the complexes is discussed in relation to the bite size of the chelating ligands; the formation constants of the beryllium(II) phthalate complexes have also been determined for this purpose. A crystalline salt of formula K₂[Be(C₄H₆(COO)₂)₂]·2H₂O has been isolated and its structure has been determined by an X-ray structure analysis. The metal atom is tetrahedrally coordinated by four oxygen atoms of the dicarboxylate ligands, the coordination polyhedron being only slightly distorted from tetrahedral.
Acute oral gallium arsenide exposure and changes in certain hematological, hepatic, renal and immunological indices at different time intervals in male wistar rats
1998, Toxicology Letters
Male albino rats were given a single oral dose of gallium arsenide (GaAs) (100, 200 or 500 mg/kg). Erythrocyte δ-aminolevulinic acid dehydratase (ALAD) activity was inhibited in all the three GaAs-exposed groups accompanied by elevated urinary excretion of ALA. A significant increase in serum aspartate aminotransferase (AST) activity, and γ-glutamyltranspeptidase (γ-GT) was observed. A significant increase in hepatic malondialdehyde (MDA) and a decrease in hepatic glutathione contents were also noted. Renal alkaline phosphatase activity, urinary ALA and protein excretion increased significantly on GaAs exposure. These changes were accompanied by significant alterations in almost all the immunological variables, with an increase in gallium and arsenic concentration in blood and soft tissues. While most of the above biochemical alterations were prominent at day 7 following single exposure to 200 and 500 mg/kg GaAs, most of the immunological indices altered with all the three doses and remained high even at day 21. The results suggest only a moderate effect of GaAs on renal and hepatic tissues. By contrast, immunological and haematological systems are the most vulnerable to the toxic effects of GaAs.
Arsenic-induced changes in certain neurotransmitter levels and their recoveries following chelation in rat whole brain
1997, Toxicology Letters
Arsenic as sodium arsenite (100 ppm in drinking water) was administered to male rats for 16 weeks. Animals were then treated either with meso-2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), dimethyl DMSA (DmDMSA), or diisopropyi DMSA (DiPDMSA) twice daily (50 mg/kg) intraperitoneally for 5 days. After 5 clays of rest period, the animals were again given a second course of chelation therapy. The animals were sacrificed subsequently for the determination of whole brain biogenic amines levels, acetylcholinesterase (AChE), monoamine oxidasc (MAO) and δ-aminolevulinic acid dehydratase (ALAD) activities. A number of biochemical parameters and arsenic concentrations in some tissues were also determined. The results suggest a significant increase in brain arsenic concentration accompanied by alterations in neurotransmitters levels following As(III) exposure. Although chelation treatment was effective in reducing As burden, the altered biochemical variables responded less favorably to chelation therapy. The DMSA-diesters, particularly DiPDMSA, produced a more pronounced increase in brain arsenic burden, as well as alterations in a few neurotransmitters. It can be concluded that the lipophilic character of As antidotes may lead to unfavorable results following intraperitoneal administration.
Biochemical and immunotoxicological alterations following repeated gallium arsenide exposure and their recoveries by meso-2,3-dimercaptosuccinic acid and 2,3-dimercaptopropane 1-sulfonate administration in rats
1996, Environmental Toxicology and Pharmacology
Efficacy of two analogues of British anti-lewisite (BAL), meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane 1-suffonate (DMPS), in depleting arsenic and gallium concentration of blood and other soft tissues, in restoring altered blood, liver and renal biochemical variables and some immunlogical indices were investigated in male rats exposed to multiple doses of gallium arsenide (GaAs). The results indicate that exposure to gallium arsenide produced a significant inhibition of blood δ-aminolevulinic acid dehydratase (ALAD) activity, an increase in urinary ALA excretion and blood zinc protoporphyrin level. Blood glutathione (GSH) contents also decreased on GaAs exposure. No influence of GaAs however, on serum transminase activity or hepatic GSH contents was noticed, although, renal alkaline phosphatase activity decreased significantly on GaAs exposure. Further, a marked influence of GaAs administration on immunological variables like relative thymus and spleen weight, spleen cellularity, antibody forming cell (AFC) response to sheep RBC and delayed type of hypersensitivity (DTH) was observed. These data indicate that multiple exposure to GaAs may produce an adverse effect on the haematopoietic, renal and immune system. Further, post exposure treatment with two thiols, meso-2,3-dimercaptosuccinic acid and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), DMPS proved more effective than DMSA in producing an effective reversal of altered immunological variables and reducing arsenic concentration of spleen, liver, kidney and blood. Biochemical variables, on the other hand, responded less favorably to the treatment of DMSA or DMPS except for a significant recovery in the activity of blood δ-aminolevulinic acid dehydratase (ALAD) following DMSA administration. The results suggest that DMPS could be an effective chelating drug for reversing most of the GaAs induced immunological alterations and reducing tissue arsenic burden.
Alterations in some hepatic biochemical variables following repeated gallium arsenide administration in rats
1996, International Hepatology Communications
Gallium arsenide (GaAs), an intermetallic compound with superior semi-conductor properties, is finding extensive application in the electronic industry. Exposure to airborne particles in the GaAs industry may pose potential health hazards to workers. However, very little information is available so far regarding the possible toxic effects of this compound. The present study was planned to investigate the dose-dependent influence of repeated gallium arsenide (GaAs) administration (50, 100 or 200 mg/kg, orally through gastric intubation, 5 days a week for 3 weeks) on some biochemical indices in blood and hepatic tissues. The results indicate a significant dose-dependent inhibition of blood δ-aminolevulinic acid dehydratase (ALAD) activity, glutathione and an elevation in zinc protoporphyrin level. Blood haemoglobin level decreased only at the two higher dose levels. The effects of GaAs administration on hepatic biochemical variables indicates only moderate adverse effects on serum glutamic oxaloacetic (GOT) and glutamic pyruvic transaminase (GPT) following exposure at the highest dose (200 mg/kg). GaAs exposure also lead to a significant inhibition of hepatic ALAD activity, an elevation in MDA formation and alkaline phosphatase activity. Most of the above alterations occurred at the 200 mg/kg dose. Dose-dependent increases in blood and hepatic arsenic concentration were also noticed. The results confirm our earlier observation that GaAs had a marked influence on the haematopoietic system while it has only moderate effect on the hepatic organ.

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Toxicology

Abstract

References (24)

Thiol antidotes effect on lipid peroxidation in mercury poisoned rats

Chem.-Biol. Interact.

Tissues sulphydryl groups

Arch. Biochem. Biophys.

Management of childhood lead poisioning

J. Pediatr.

DMSA and DMPS — water soluble antidotes for heavy metal poisoning

Annu. Rev. Pharmacol. Toxicol.

meso-2,3- Diemercaptosuccinic acid: chemical, pharmacological and lexicological properties of an orally effective metal chelating agent

Annu. Rev. Pharmacol. Toxicol.

European standardized method for the determination of δ-aminolevulinic acid dehydratase activity in blood

Z. Klin. Chem. Klin. Biochem.

Rapid determination of beryllium by a direct reading atomic absorption spectrophotometer

Am. Ind. Hyg. Assoc. J.

Estimation of haemoglobin by the alkaline haematin method

Br. Med. J.

Antidotal effects of dimercap-tosuccinic acid

J. Appl. Toxicol.

The colorimetric determination of phosphates

J. Biol. Chem.

Osteosarcoma from intravenous beryllium in rabbits

Occupational lead exposure in Denmark. Screening with the haematofluorometer

Br. J. Ind. Med.

Cited by (21)

Chelation Treatment During Acute and Chronic Metal Overexposures-Experimental and Clinical Studies

Complexes of beryllium(II) with substituted malonates. Crystal structure of K<inf>2</inf>[Be(C<inf>4</inf>H<inf>6</inf>(COO)<inf>2</inf>) <inf>2</inf>]·2H<inf>2</inf>O

Acute oral gallium arsenide exposure and changes in certain hematological, hepatic, renal and immunological indices at different time intervals in male wistar rats

Arsenic-induced changes in certain neurotransmitter levels and their recoveries following chelation in rat whole brain

Biochemical and immunotoxicological alterations following repeated gallium arsenide exposure and their recoveries by meso-2,3-dimercaptosuccinic acid and 2,3-dimercaptopropane 1-sulfonate administration in rats

Alterations in some hepatic biochemical variables following repeated gallium arsenide administration in rats