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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↗
PubMed1993

Regulation of contraction-stimulated system A amino acid uptake in skeletal muscle: role of vicinal sulfhydryls.

Functional vicinal sulfhydryls are essential for insulin-stimulated system A neutral amino acid uptake in the rat epitrochlearis muscle. In skeletal muscle, system A uptake is also activated by contractile activity. Therefore, the purposes of this study were to characterize the stimulation of system A activity by contractions induced by electrical stimulation in vitro, and to assess the role of vicinal sulfhydryls in this process. System A activity in the isolated epitrochlearis muscle was measured using the nonmetabolizable analogue alpha-(methylamino)isobutyric acid (MeAIB). Contractions increased MeAIB uptake by increasing the apparent maximal velocity (Vmax), with no alteration in the apparent Km. The maximal stimulatory effects of insulin and contractions on MeAIB uptake were completely additive, demonstrating that these two stimuli exert their effects via different mechanisms. Phenylarsine oxide (PAO), a vicinal sulfhydryl antagonist, at greater than 20 mumol/L inhibited basal and contraction-stimulated MeAIB uptake by approximately 50% and 70%, respectively, by decreasing Vmax, with no change in Km. Both inhibitory effects were completely prevented by cotreatment with the vicinal dithiol dimercaptopropanol (DMP), indicating the effects were mediated by interactions with vicinal sulfhydryls. Contraction-stimulated MeAIB uptake was rapidly (half-time, approximately 7 minutes) reversed by the addition of PAO. These results (1) define conditions under which contraction-stimulated system A amino acid uptake can be studied in an isolated mammalian skeletal muscle preparation, and (2) indicate that vicinal sulfhydryls are essential for stimulation of system A activity by muscle contractions.

Amino Acids↗
PubMed1979

Lead poisoning. A comprehensive review and report of a case.

Lead, a ubiquitous heavy metal which has realized increased use, can cause poisoning by environmental contamination in either its organic or its inorganic form. Lead poisoning can be either acute or chronic, with the latter being the more common. The clinical signs and symptoms of lead poisoning are nonspecific, resulting in a difficult diagnostic problem, especially when it is not industrially related. On occasions, the dentist or oral surgeon may be the first to see an afflicted patient because of oral manifestations.

Adult↗
PubMed1983

BAL increases the arsenic-74 content of rabbit brain.

The 74As content of the brain of rabbits was doubled following administration of BAL (2,3-dimercapto-1-propanol). DMPS (2,3-dimercapto-1-propanesulfonic acid, sodium salt), however, decreased the rabbit brain arsenic concentration. The use of BAL as the drug of choice for treatment of arsenic intoxication should be viewed with caution and re-examined.

Animals↗
PubMed1983

Influence of chelating agents on the distribution and excretion of cadmium in rats.

The effects of the chelating agents CaNa2-ethylenediaminetetraacetate (EDTA), CaNa3-diethylenetriaminepentaacetate (DTPA), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropanol (BAL), and 2,3-dimercaptopropane-1-sulfonate (DMPS) and of the lipophilic chelating agents Puchel, Puchel-bisamidocysteineethyl ester (Puch-D), and EDTA-bis-amidocysteineethyl ester (EDTA-D) on the distribution of iv injected Cd were studied in male Sprague-Dawley rats. The chelating agents were injected iv as single doses given 10 sec, 1 hr, or 3 hr after 3 mumol/kg Cd + 115mCd. When the chelating agents were injected within 10 sec after the metal, all agents reduced the total body cadmium burden by varying extents ranging from 3% of that in untreated control rats after 0.01 mmol BAL/kg to 94% following 0.1 mmol DTPA/kg. When given 1 hr after Cd injection, the efficacy of all the agents tested was markedly reduced or abolished; at this time only Puchel and Puch-D provoked significant reductions in the body burden of Cd by 21 and 32%, respectively. When treatment was delayed until 3 hr after Cd injection, only Puch-D was able to reduce the body and liver burden of the metal by 14 and 9%, respectively. Combined treatment with Puchel + DTPA, BAL + DTPA, or BAL + DMPS did not enhance Cd removal to an extent greater than that expected from the equivalent dose of the more effective agent of that pair alone. Repeated administration of DTPA, 20 X 0.1 mmol/kg, during 4 weeks by ip or po administration of the same dose in the drinking water over 4 weeks, was no no more effective than the first dose of the chelating agent alone. Gel chromatographic studies of the distribution of Cd among the proteins of the liver cytosol in treated and untreated animals indicate that neither DTPA nor Puchel was able to release Cd from the metallothionein complex.

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↗
PubMed1984

N-(2,3-dimercaptopropyl)phthalamidic acid: protection, in vivo and in vitro, against arsenic intoxication.

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 approximately 2.5-fold following two ip injections of 0.20 mmol DMPA/kg. The effectiveness of DMPA in reducing the toxicity of NaAsO2 was further demonstrated by its reversal of the sodium arsenite inhibition of pyruvate dehydrogenase multienzyme complex (PDH) activity in vitro. Similarly, in an in vivo experiment in which mice received 0.10 mmol NaAsO2/kg, and 30 min later were given 0.05 or 0.10 mmol/kg DMPA, there was a rapid recovery of PDH activity. The distribution of 74As in the tissues of male New Zealand rabbits was altered following im injection of 0.20 mmol/kg DMPA. Under these conditions, the tissue concentration of 74As was significantly decreased. For all tissues tested, the 74As content decreased by at least 50% as compared to that of untreated controls. DMPA was effective also in increasing both urinary and fecal excretion of arsenic. The stability of aqueous solutions of DMPA varies with the pH of the solution. DMPA is more stable in acid solution.

Animals↗
PubMed1985

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

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

Animals↗
PubMed1986

Comparative effects of three chelating agents on distribution and excretion of cadmium in rats.

Sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC), which was newly synthesized, 2,3-dimercaptopropanol (BAL), and N-methyl-D-glucamine dithiocarbamate (NMG-DTC) were compared for their relative efficacies in the distribution and excretion of cadmium in rats exposed to cadmium. Rats were injected ip with 109CdCl2 (1 mg Cd and 10 microCi 109Cd/kg) and 3 days later, they were treated with the chelating agents (400 mumol/kg) every other day for 2 weeks. These chelating agents were effective in removing cadmium from the body without increasing the amount of cadmium in the kidney. After treatment with these chelating agents, cadmium was excreted mainly in the feces through the bile and the fecal excretion of cadmium by NBG-DTC was significantly larger than that by BAL or NMG-DTC. The hepatic cadmium content after treatment with NBG-DTC was much more decreased than that with BAL or NMG-DTC. The renal cadmium content was decreased only after treatment with NBG-DTC. These chelating agents did not result in the redistribution of cadmium to brain, testes, and heart. The growth of rats was little retarded by treatment with NBG-DTC and NMG-DTC, but was retarded by treatment with BAL. The treatment with NBG-DTC decreased the tissue amounts of Zn, Fe, and Mn to a small extent as compared with the treatment with cadmium alone. The results of this study reveal that the injection of NBG-DTC to rats pretreated with cadmium can more effectively remove cadmium from the body without the mobilization of cadmium to the kidney, the critical organ in cadmium toxicity, and without redistribution of cadmium to other tissues such as brain, testes, and heart, than injection of BAL and NMG-DTC.

Animals↗
PubMed1987

Inhibition of rat heart mitochondrial respiration by cadmium chloride.

Mitochondria were isolated from hearts obtained from adult male Sprague-Dawley rats by two-part differential centrifugation of heart homogenates. Time-dependent (0-120 sec) and concentration-dependent (0-10 microM CdCl2) effects of cadmium on pyruvate-malate-supported state 3 and state 4 respiration were measured in a constant temperature reaction chamber at 37 degrees C, according to established procedures. The ID50 for cadmium chloride on state 3 respiration was determined to be 4.2 microM. The inhibition produced by cadmium chloride in heart mitochondria was compared, using identical procedures, to the effects induced by two compounds, sodium atractyloside and potassium cyanide, which are known to alter mitochondrial respiration at specific sites. The calculated ID50 values for these agents in heart mitochondria were 1.8 and 16 microM, respectively. The concentration-dependent inhibition of mitochondrial respiration induced by either cadmium chloride or potassium cyanide was maintained in the presence of 50 microM carbonyl cyanide m-chlorophenylhydrazone (CCCP), a known uncoupling agent. In contrast, sodium atractyloside did not block the uncoupling effect of 50 microM CCCP. In addition cadmium chloride was also shown to inhibit CCCP-uncoupled mitochondrial respiration. The cadmium-induced inhibition of mitochondrial respiration was reversed partially by cysteine and completely by 2,3-dimercaptopropanol. The results of the present study indicate that, at all concentrations, cadmium chloride acted solely as an inhibitor of rat heart pyruvate-malate-supported mitochondrial respiration. These findings suggest a possible mechanism for the reported disturbances in myocardial metabolism and function that occur in conjunction with acute and chronic cadmium exposure in humans and experimental animals.

Animals↗
PubMed1989

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

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

Animals↗