Biomedical subjects

G R Gale

Publications and source records attributed to G R Gale.

At least 19 recordsLinked to original sources

PubMed1994

Effect of chelate treatments on kidney, bone and brain lead levels of lead-intoxicated mice.

The effects of chelating agent treatment with meso-2,3-dimercaptosuccinic acid (DMSA), Na2CaEDTA, Na2ZnEDTA, and Na3ZnDTPA on the organ lead levels of lead-loaded mice have been determined. At 1 mmol/kg/day i.p., all caused reductions in the lead levels of the kidney after four injections, but only Na2CaEDTA produced a significant reduction in brain lead. All chelating agents caused significant reductions in kidney and brain lead levels when administered at a daily dose of 1 mmol/kg/day for eight days, but only DMSA reduced the bone lead level. In animals given 50 mg Pb/kg or 100 mg Pb/kg, the administration of Na2CaEDTA or DMSA at 1 mmol/kg/day x 8 produced significant reductions in kidney, bone and brain lead levels, but DMSA produced greater reductions of bone lead in both groups and of kidney lead in the group given 100 mg Pb/kg. An examination of published data describing the effect of chelating agent treatment on brain lead levels indicates that DMSA produces a reduction in brain lead levels under all conditions examined to date.

Animals↗

PubMed1994

Cadmium mobilization by monoaralkyl- and monoalkyl esters of meso-2,3-dimercaptosuccinic acid and by a dithiocarbamate.

Syntheses and relative cadmium mobilizing properties are described for three new monoaralkyl esters (HOOCCH(SH)CH(SH)COOR, where R = phenylethyl ((CH2)2C6H5), MPhEDMS; R = 3-phenylpropyl ((CH2)3C6H5), MPhPDMS; and R = 2-phenoxyethyl ((CH2)2OC6H5). MPhOEDMS) of meso-2,3-dimercaptusuccinic acid. These were prepared by the reaction of the corresponding alcohol with meso-2,3-dimercaptosuccinic acid (DMSA) in aqueous HCl. When administered intraperitoneally to cadmium-loaded mice at 0.50 mmol/kg/day for four consecutive days, all induced significant reductions in the whole body cadmium levels. MPhEDMS, 60%; MPhPDMS, 66%; and MPhOEDMS, 58% in comparison with control levels. At the same dosage monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and a dithiocarbamate, sodium N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate++ + (BLDTC) induced reductions of 65% and 57%, respectively. Hepatic and renal cadmium were also depleted significantly, while brain cadmium levels were unchanged. These compounds induced a significant reduction in the cadmium levels of the spleen, and one, MPhOEDMS, produced a 10% decrease in pancreatic cadmium. The manner in which the later injections removed smaller fractions of the total body cadmium is consistent with a bodily distribution of these compounds by which they are concentrated primarily in the kidneys and the liver, with much smaller amounts reaching other organs. It is proposed that these compounds enter renal and hepatic cells through an anion transport system.

Animals↗

PubMed1993

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

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

Animals↗

PubMed1992

Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid.

The following six monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) were synthesized and evaluated for relative activities in mobilizing lead from kidneys and brains of lead-bearing mice: n-propyl (Mn-PDMS), i-propyl (Mi-PDMS), n-butyl (Mn-BDMS), i-butyl (Mi-BDMS), n-amyl (Mn-ADMS) and i-amyl meso-2,3-dimercaptosuccinate (Mi-ADMS). DMSA was used as a positive control. When each was administered intraperitoneally (i.p.) as a single dose of 2.0 mmol/kg, DMSA lowered the kidney lead concentration 52%, while the monoesters effected reductions of 54-75%. Mn-ADMS was toxic at this dose. DMSA lowered the brain lead level 20% when given as a single dose, while the monoesters conferred reductions of 64-87%. When given as 5 daily i.p. injections at 0.5 mmol/kg, DMSA reduced the kidney lead concentration 45%, while the monoesters caused reductions of 56-73%. DMSA lowered the brain lead concentration 35% on the 5-day treatment regimen, while the monoesters evoked reductions of 59-75%. Mi-ADMS was equally effective when given orally or i.p. The i.p. LD50 value of this analog in mice is 3.0 mmol/kg, a value which lies between the reported LD50 doses of DMSA (16.0 mmol/kg) and dimercaprol (1.1 mmol/kg). It is suggested that the ability of these monoesters to cross cell membranes may account for their superiority to DMSA in mobilizing brain lead in this animal model.

Animals↗

PubMed1992

N-benzyl-N-lactyl dithiocarbamate treatment of mice after chronic cadmium administration.

Administration of N-benzyl-N-lactyl dithiocarbamate (BLDTC) to mice after chronic cadmium (Cd) administration evoked a prompt, dose-dependent reduction of the whole body burden; 75% of the retained Cd was mobilized and excreted after 20 i.p. injections of BLDTC at 1.0 mmol/kg/injection. This same dose regimen produced 71% and 98% reductions of the renal and hepatic Cd concentrations, respectively. There was no reduction by BLDTC of the endogenous level of any of seven other metals measured: iron, magnesium, selenium, copper, calcium, zinc, and manganese. Renal proximal tubular damage in mice which received Cd followed by BLDTC was much less than that observed in kidneys from mice which received Cd alone. Chronic Cd administration led to substantial epithelial vacuolar damage to renal distal tubules, and this process was not apparently reversed or antagonized by BLDTC treatment to the extent observed in proximal tubules.

Animals↗

PubMed1992

Cadmium mobilization in vivo by intraperitoneal or oral administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid in the mouse.

The relative activities of a series of nine monoalkyl esters of meso-2,3-dimercaptosuccinic acid have been examined as agents for the mobilization of cadmium from mice one week after intraperitoneal administration of cadmium chloride. Eight of these are newly synthetized; all are of the type ROOCCH(SH)CH(SH)COOH, were R = Me, MMDMS; R = C2H5, MEDMS; R = (CH2)2CH3, Mn-PDMS; R = CHMe2, Mi-PDMS; R = (CH2)3CH3, Mn-BDMS; R = CH2CHMe2, Mi-BDMS; R = (CH2)4CH3, Mn-ADMS; R = (CH2)2CHMe2, Mi-ADMS; and R = (CH2)5CH3, Mn-HDMS. All are soluble in dilute sodium bicarbonate solutions and can be administered as aqueous solutions. Cadmium mobilization data were collected on each compound using mice previously loaded with cadmium; the monoesters were administered at a level of 0.40 mmol/kg intraperitoneally daily for five days. Data on whole body cadmium mobilization indicated that the monoester with the isoamyl group was the most effective under the conditions used. The relative whole body cadmium mobilization increased with the number of carbon atoms in the alkyl group of the monoester up to C5 and then decreased for the C6 compound. Cadmium removal from the kidneys and liver was also measured. It was found that the monoisoamyl ester was the most effective in removing cadmium from both the liver and the kidneys. The monoisoamyl ester also proved to be very effective in mobilizing cadmium from both the liver and the kidneys when given orally. This is the first compound which is reported capable of mobilizing cadmium in vivo from aged deposits after oral administration.

Animals↗

PubMed1992

Evidence of active transport of cadmium complexing dithiocarbamates into renal and hepatic cells in vivo.

A study was made of the effects of certain inhibitors of transport systems on the actions of four cadmium (Cd) complexing N,N-disubstituted dithiocarbamates (DTCs) in mobilizing murine renal and hepatic Cd in vivo. Probenecid, the prototypical antagonist of organic anion transport in the kidney, when given 1 hr prior to each DTC, sharply suppressed the DTC-induced reduction of renal Cd but was virtually without effect on mobilization of Cd from liver. Sulfinpyrazone, which blocks tubular reabsorption of uric acid and also inhibits transport of a variety of organic acids, inhibited markedly the mobilization of both renal and hepatic Cd by DTCs. Phlorizin, an inhibitor of tubular sugar reabsorption, did not affect the Cd mobilizing actions of DTCs in any consistent fashion. We propose that the high degree of selectivity of DTCs in mobilizing renal and hepatic Cd is dependent, at least in part, upon active transport of DTCs into these tissues via the organic anion transport systems. This report presents the first evidence that compounds of the (R)2NCSS- class may gain access to intracellular space by an active, carrier-mediated process.

Animals↗

PubMed1992

Enhanced mobilization of hepatic cadmium in mice upon coadministration of an N, N-disubstituted dithiocarbamate and an alkyl monoester of dimercaptosuccinate.

Oral (po) administration of mono-iso-amyl (2,3-dimercapto) succinate (Mi-ADMS), 0.5 mmol/kg for three consecutive days, to mice previously injected with cadmium (Cd) chloride reduced the whole body Cd burden 34%. Intraperitoneal (ip) administration of N-iso-amyl-N-glucaminedithiocarbamate (i-AmGDTC) by the same regimen reduced total body Cd 41%. Coadministration of the two compounds reduced the whole body Cd burden 60% (p less than 0.05). The liver Cd concentration was reduced 56% and 50%, respectively, by Mi-ADMS given po and i-AmGDTC given ip, each at 0.5 mmol/kg for three consecutive days. Coadministration of the two chelators reduced the liver Cd concentration 90% (p less than 0.05). The kidney Cd concentration was reduced 10% by Mi-ADMS alone, and 60% by i-AmGDTC alone, but there was only a 47% reduction when the two chelators were coadministered, probably as a result of redistribution of mobilized hepatic Cd to the kidneys. As 50-55% of the administered Cd is sequestered in the liver in this mouse model, it is concluded that coadministration of the two chemical classes of Cd complexing agents may offer a therapeutic advantage over administration of either agent alone.

Administration, Oral↗

PubMed1992

Monoisoamyl meso-2,3-dimercaptosuccinate: interaction with metallothionein-bound cadmium in vitro and evidence of active transport into renal and hepatic cells in vivo.

Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and the unesterified 2,3-dimercaptosuccinic acid (DMSA) were evaluated for relative reactivities against metallothionein (MT)-bound cadmium (Cd) in vitro by elution of the reaction products through Sephadex G-75 gel. After 3 hr of incubation, Mi-ADMS removed about 70% of the Cd from Cd-MT, and a new peak emerged which corresponded to that obtained by elution of a 2:1 molar mixture of Mi-ADMS and Cd. Only about 15% of the Cd was removed from Cd-MT by DMSA. After 24 hr of incubation with Mi-ADMS, no evidence remained of the presence of Cd-MT; all of the Cd was recovered in a very high molecular weight fraction and in a fraction corresponding to Cd ion. In contrast, after 24 hr of incubation with DMSA, 25% of the Cd was still present as Cd-MT, while the remainder eluted in a fraction corresponding to a 2:1 molar complex of DMSA and Cd. When Mi-ADMS was administered to Cd-bearing mice which had received an inhibitor of organic anion transport, probenecid (PBC) or sulfinpyrazone (SPZ), prior to administration of the monoester, there was a marked attenuation of the Cd mobilizing actions of Mi-ADMS as reflected in whole body Cd levels. Analysis of organ Cd concentrations revealed that PBC blocked primarily the mobilization of renal Cd by Mi-ADMS, while the principal action of SPZ in antagonizing the action of Mi-ADMS was on hepatic Cd mobilization. It was concluded that Mi-ADMS has a higher affinity for Cd in Cd-MT than does DMSA, and that the access of Mi-ADMS to intracellular Cd is, at least in part, mediated by the organic anion transport system.

Animals↗

PubMed1991

Comparative iron mobilizing actions of deferoxamine, 1,2-dimethyl-3-hydroxypyrid-4-one, and pyridoxal isonicotinoyl hydrazone in iron hydroxamate-loaded mice.

A comparison was made of the actions of deferoxamine (DFX), 1,2-dimethyl-3-hydroxypyrid-4-one (L1), and pyridoxal isonicotinoyl hydrazone (PINH) in mobilizing and promoting excretion of iron in mice loaded with iron-acetohydroxamic acid complex. DFX was given ip, while L1 and PINH were given po. Each was given daily for four days at 300 mg/kg/day, and total excreta were collected 24 hr after each administration. Total iron excreted over the 4-day period, expressed as micrograms/mouse, were: Controls, 26; PINH-treated, 31; DFX-treated, 162; and L1-treated, 208. Measurements of iron in selected organs 96 hr after the last administration of each compound revealed that treatment with L1 and DFX induced significant reductions of iron concentrations in kidneys (16% and 17%, respectively) and in pancreas (18% and 19%, respectively). In addition, L1 treatment led to a significant reduction in the liver iron burden (11%), an action not seen after treatment with DFX. None of the compounds reduced iron concentrations in heart, the most critical organ for toxicity of transfusional siderosis. The synthetic routes for preparation of L1 and PINH are described in detail.

Animals↗

PubMed1990

Selective removal of cadmium from aged hepatic and renal deposits: N-substituted talooctamine dithiocarbamates as cadmium mobilizing agents.

The preparation and examination of three dithiocarbamates derived from N-substituted D-gluco-L-talooctamine reveals that the 4-methoxybenzyl derivative (MeOBGD) is superior to any previously prepared dithiocarbamates as an agent for the mobilization of aged intracellular hepatic cadmium deposits from mice. All of these compounds are also quite effective in reducing whole body burdens of cadmium. The use of these compounds does not result in any increase in the cadmium content of the brain. The selection of these chelating agents for synthesis was suggested by an analysis of the log dose-response curves for the mobilization of renal cadmium by previously studied dithiocarbamates. This revealed that the slope of the percentage renal cadmium mobilized vs the log dosage curve is determined to a considerable extent by the sum of the Hansch pi parameters for the substituents, while the intercept is largely determined by the molecular weight of the compound. The implication of such a correlation is that the ability of a chelating agent to remove cadmium from its aged deposits is determined to some extent by its molecular weight, provided the polarity of the overall molecule is appropriate.

Aging↗

PubMed1990

The mobilization of intracellular cadmium by alkoxyethyl esters of meso-2,3-dimercaptosuccinic acid.

The cadmium mobilizing properties of two newly synthesized esters of meso-2,3-dimercaptosuccinic acid in mice have been examined. They are: di(2'-methoxyethyl) meso-2,3-dimercaptosuccinate ([-CH(SH)COOCH2CH2OR]2, R = CH3; MEDMS), and di(2'-ethoxyethyl) meso-2,3-dimercaptosuccinate ([-CH(SH)COOCH2CH2OR]2, R = CH2CH3; EEDMS), conveniently prepared from dimercaptosuccinate acid with 2-methoxyethanol and 2-ethoxyethanol, respectively. Mobilization studies in mice of aged in vivo cadmium deposits using five ip injections of 0.40 mmol/kg of each chelator in peanut oil clearly indicate that both compounds, MEDMS and EEDMS, are significantly superior to 2,3-dimercaptopropan-1-ol (BAL) in depleting the whole body burden of cadmium. The reductions caused by MEDMS and EEDMS were approximately 20 and 26%, respectively, whereas under similar dosage regimens BAL effected about only a 12% reduction. The esters were neither equal nor superior to BAL for the reduction of renal cadmium levels, MEDMS being the least effective. For the mobilization of hepatic cadmium deposits, both were quite promising (MEDMS, 20%; EEDMS, 34% reduction) compared to BAL (only 2% reduction). There was no accumulation of cadmium with either MEDMS or EEDMS in any of the other organs examined--spleen, testes, pancreas, and particularly the brain. These compounds enhance the fecal excretion of cadmium by a factor of 25- to 40-fold but have very little effect on the urinary excretion of this element. The present study reveals that the order of overall efficacy is EEDMS greater than MEDMS greater than BAL, considering the liver and whole body burdens of cadmium, but BAL greater than EEDMS greater than MEDMS in terms of the efficacy in reducing cadmium levels in the kidneys.

Animals↗

PubMed1990

Structural influences on intracellular cadmium mobilization by dithiols.

An examination of 5 dithiols, N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA), benzene-1,2-dithiol (BDT), toluene-3,4-dithiol (TDT), alpha, alpha'-dimercapto-o-xylene (DOX), and 4,5-dimethyl-alpha,alpha'-dimercapto-o-xylene (DDOX), reveals that these compounds are all inferior to previously reported compounds as agents for the in vivo mobilization of cadmium from its intracellular sites, although all possess sulfhydryl groups capable of reacting with cadmium. The results demonstrate the considerable importance of those parts of the molecule which do not participate directly in the formation of chelate rings in the determination of the ultimate behavior of such compounds in vivo.

Animals↗

PubMed1990

Schedule dependency of a cadmium-complexing dithiocarbamate analog in mice.

A number of dosing regimens was assessed to determine the optimum schedule of administration of N-(4-methoxybenzyl)-N-dithiocarboxy-D-glucamine (MeOBDCG) in depleting whole-body, renal and hepatic levels of metallothionein-bound cadmium (Cd) in mice. A comparison of 4.0 mmol/kg given as a single injection versus 0.5 mmol/kg given as 8 hourly injections revealed the latter regimen to be superior in reducing renal Cd levels, but less effective than a bolus dose in lowering hepatic Cd concentrations. Administration of 1.33 mmol/kg for 3 consecutive days or 0.8 mmol/kg for 5 days effected a more extensive depletion of renal Cd concentrations than did a single injection of 4.0 mmol/kg. Three injections of 1.0 mmol/kg given at 4- to 7-day intervals were generally more effective in reducing renal Cd concentrations than were 3 consecutive daily injections in mice which had low or moderately high total Cd burdens. The lowest effective dose of MeOBDCG in lowering whole-body, liver and kidney Cd levels when given repetitively was about 0.2 mmol/kg. While schedule variations did not alter appreciably the whole-body Cd reductions at any given total dose of MeOBDCG, repetitive dosing schedules in which injections were given at intervals of several days rather than daily were typically more effective in reducing renal Cd levels. Based upon consideration of pharmacological response as influenced by body surface area, it was calculated that doses of MeOBDCG of the order of 2.0 g/d may be effective in reducing renal Cd levels in individuals with chronic renal dysfunction secondary to chronic Cd intoxication.

Animals↗

PubMed1990

Glutathione status, glutathione monoisopropyl ester, and cadmium metabolism in mice.

Glutathione monoisopropyl ester (GSHMI) was synthesized for an investigation of its interactions with cadmium (Cd) in mice. When administered ip prior to the injection of lethal doses of Cd given by the ip or sc route, it did not reduce Cd-induced mortality. When given to Cd-bearing mice it did not promote mobilization of Cd from metallothionein-bound stores in liver, kidneys, spleen, testes, pancreas, or brain. When given at a dose of 6.0 mmol/kg 2 hr prior to administration of Cd, GSHMI enhanced Cd accumulation in kidneys, liver, spleen, and testes, and reduced the accumulation of the metal in brain. When 4.0 mmol/kg of the ester were given at various intervals prior to Cd administration, the major actions observed were substantial increases in Cd concentrations ultimately attained in kidneys and liver at most time intervals examined. Reductions of Cd accumulation were found only in liver and pancreas, and only when GSHMI treatment preceded Cd administration by 30 min. Reduction of endogenous GSH levels by administration of L-buthionine-(S,R)-sulfoximine (BSO) led to moderate increases in Cd accumulation in kidneys and pancreas; Cd deposition was reduced in spleen, testes, heart, lungs, and brain. BSO pretreatment led to only slight or no change in liver Cd accumulation. Sephadex G-75 gel filtration chromatography revealed that GSHMI pretreatment led to only a moderate and transient increase in hepatic Cd-metallothionein content when measured 2 hr after Cd administration; when assessed 1 hr and 3 hr post-Cd, elution profiles of extracts from livers of GSHMI-pretreated mice were indistinguishable from control profiles. We conclude that GSHMI is not an effective agent for the control of Cd toxicity.

Animals↗

PubMed1990

Combinations of 4-hydroperoxycyclophosphamide (4-HC) and cisplatin for bone marrow purging in autologous marrow transplantation: an update.

We are studying the usefulness of combinations of 4-HC and cisplatin as a potential purging regimen for autologous bone marrow transplantation. In all of our studies, in vitro cytotoxicity was determined by clonogenic assay, and drug interaction was quantitated using the multiple drug-effect analysis method. The cells were incubated for one hour (4-HC) and/or 4 hours (cisplatin). We found that the drugs in combination had cytotoxic synergism against human leukemia cell lines (K-562 and Raji). The synergism was sequence-dependent (cells must be exposed to 4-HC first), was present at various molar ratios of the drugs, and most pronounced at high levels of cell kill. We also found that the drugs had cytotoxic synergism against normal human marrow progenitors (CFU-GM). However, the leukemic cells were approximately 55 times more sensitive to the combination than CFU-GM. In a murine system, the drugs were synergistic against L1210 leukemia cells and normal murine CFU-GM, but L1210 cells were at least 130 times more sensitive to the combination than CFU-GM. To determine the ability of L1210 cells to grow in vivo after exposure to the drugs, BDF1 mice were injected with 2 x 10(4) cells which had been incubated with 4-HC and/or cisplatin. The survival time of untreated controls was 13 +/- 2.8 days. For treated groups, the cure rates after 50 days of observation were 33% (4-HC, 40 uM), 0% (cisplatin, 8 uM), and 100% (4-HC + cisplatin). Finally, at concentrations resulting in equivalent toxicity to marrow CFU-GM, cisplatin seemed to be more toxic to murine spleen blast colony forming cells (CFC-BC) than 4-HC. The drugs in combination appeared to have at least additive toxicities against CFC-BC.

Animals↗

PubMed1989

The rate of the in vivo dithiocarbamate-induced mobilization of hepatic and renal cadmium deposits.

The dithiocarbamate-induced removal of aged cadmium from intracellular sites in the kidneys and liver of mice has been followed as a function of time. The processes are quite rapid with the entire course of the cadmium-removal process being completed in 60-90 min. An examination of the rates at which a dithiocarbamate removes cadmium from hepatic and renal deposits in vivo and from metallothionein in vitro, suggests strongly that the processes are similar. A common mechanism is proposed for both processes which involves the direct attack by the dithiocarbamate on cadmium ion incorporated into metallothionein. Such a mechanism is consistent with the similarities in rates and the degree of overall mobilization of cadmium by the same dithiocarbamate both in vitro and in vivo. The administration of 1 mmol/kg of sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate (MeOBDCG) to cadmium-loaded mice leads to a reduction of in vivo renal and hepatic cadmium levels of 45% and 30%, respectively, over a period of only 1 h. Previously the incubation of metallothionein in vitro in the presence of 1 mmol/l of MeOBDCG was found to lead to the reduction of the cadmium content of metallothionein of approximately 60% over a period of 1 h. The administration of higher doses of this compound (2 mmol/kg and 4 mmol/kg) to cadmium-loaded mice led to an even more rapid and more extensive removal of cadmium from both the liver and the kidney. The major factors which limit the ability of dithiocarbamates to mobilize cadmium from in vivo sites appear to be molecular structural features which hinder or prevent the access of the dithiocarbamates to the intracellular sites at which the majority of aged cadmium deposits are held.

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↗