Distribution of chromium in poisoned rats.

The effect of dose and duration of treatment with chromium on its distribution in certain vital organs and the blood of rats has been investigated. The accumulation of metal was highest in liver and kidneys, followed by testes, brain and blood and was rather more dependent on the dose than on the duration of exposure. The sub-cellular distribution in liver revealed greater concentration of the metal in the nuclear fraction than in the mitochrondrial or the post mitochondrial fraction. The uptake of the metal by the mitochondrial fraction however, increased with the increase in the dose of chromium from 1 mg/kg to 2 or 3 mg/kg.

Influence of metal chelators on metalloenzymes.

The influence of chelating agents (1 mmol/kg/day X 6,i.p.) on trace metal mobilization and activities of certain metalloenzymes was investigated in rats. Calcium disodium ethylenediamine tetraacetate (CaNa2EDTA) and calcium trisodium diethylenetriamine pentaacetate (CaNa3DTPA) enhanced urinary excretion of Zn, while sodium 2,3-dimercaptopropane-1-sulfonate (NaDMPS) and sodium diethyldithiocarbamate (NaDDC) increased that of Cu. The activity of Zn-metalloenzymes-blood delta-aminolevulinic acid dehydratase (delta-ALA-D), plasma alkaline phosphatase (ALP) and that of Cu-metalloenzyme-plasma amine oxidase was decreased as a consequence of chelation therapy. However, hepatic levels of delta-ALA-D, ALP and alcohol dehydrogenase remained unaffected by chelation. The activity of hepatic Fe-metalloenzyme-catalase was increased by polyaminocarboxylic acids and lowered by thiol chelators. The metal chelators decreased the hepatic glutathione levels.

Chelation in metal intoxication. XXXIV. Mixed ligand chelation in lead poisoning.

The effectiveness of alpha-mercapto-beta-(2-furyl)acrylic acid (MFA) and N-benzyl-N-dithiocarboxy-D-glucamine (NaB), used in combination, in the mobilization and excretion of lead was investigated in rats. Male Wistar rats received 10 mg Pb/kg as lead acetate intragastrically daily for 6 weeks. The lead-exposed rats were treated with either MFA or NaB or both 200 mumol/kg i.p., each, daily for 3 days. Both chelating agents provoked significant urinary and faecal excretion and lowered the soft-organ lead burden. However, combined therapy did not elicit any additive or synergistic response.

Chelation in metal intoxication. IX. Influence of amino and thiol chelators on excretion of manganese in poisoned rabbits.

The effect of two polyamino-polycarboxylic acids, N-(2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA) and diethylenetriamine penta-acetic acid (DTPA) and two thiol-chelating agents, sodium diethyldithiocarbamate (DDC) and dimercaptosuccinic acid (DMS) on the excretion of manganese (Mn) in rabbits given Mn i.p. was studied in order to investigate the affinity of this metal to N, O and S-containing compounds. HEDTA and DTPA were effective, and DDC and DMS were ineffective, in enhancing urinary and faecal excretions of Mn, indicating a greater binding capacity of Mn with chelators having N and O, than with those having S as electron donating centres.

Chelation in metal intoxication XXVI : Influence of thiamine on the therapeutic efficacy of calcium disodium edetate in lead intoxication.

The effect of pretreatment and simultaneous treatment with thiamine on therapeutic efficacy of calcium disodium edetate (CaNa2EDTA) in lead intoxication was investigated in rats. The animals exposed to Pb as Pb (CH3COO)2·3 H2O through drinking water (0.1%) for 8 wk were treated with either saline, thiamine-HCl (sc), CaNa2EDTA (ip), or thiamine-HCl plus CaNa2EDTA, for 3 d or thiamine-HCl for 3 d followed by thiamine, then HCl plus CaNa2EDTA for a further 3 d. The Pb exposure caused significant accumulation of Pb in liver, kideny, and brain, inhibition in the activity of blood δ-amino-levulinic acid dehydratase (δ-ALAD), and increase in levels of urinary δ-aminolevulinic acid, homovanillic acid (HVA), vanillyl mandelic acid (VMA), brain HVA and VMA. The brain δ-ALAD and lipomide dehydrogenase remained unaffected by Pb. Thiamine significantly enhanced the urinary excretion of Pb by CaNa2EDTA, but only marginally influenced the efficacy of CaNa2EDTA to either mobilize tissue Pb or reverse the biochemical alterations.

Interrelationship between iron deficiency and lead intoxication (Part 1).

The influence of lead exposure, iron deficiency, or their combination on certain biochemical parameters in blood, plasma, and urine of rats was investigated in an attempt to identify the specific diagnostic tests of the two conditions and to draw a possible interrelationship between the two factors. The decrease in blood-glutathione peroxidase activity, -packed cell volume, plasma-ceruloplasmin, and-Fe levels and increase in urinary excretion of delta-aminolevulinic acid, plasma-cholesterol, and-total Fe binding capacity occur under Fe deficiency as well as Pb intoxication. However, increase in the activity of blood delta-aminolevulinic acid dehydratase (ALAD) without any change in blood zinc protoporphyrin (ZPP) level appears to be a specific effect of Fe deficiency that could be distinguished from Pb intoxication, a condition characterized by the inhibition in blood ALAD activity accompanied by an increase in blood ZPP level. The linear regression analysis of the data showed that the blood Pb and plasma free cholesterol levels increase with the decrease in plasma Fe level.

Interrelationship between iron deficiency and lead intoxication (Part 2).

The influence of dietary iron deficiency, lead exposure or their combination on certain enzymes, and the accumulation of Pb and essential metal levels in vital organs of rats was investigated. Iron deficiency caused alterations in the activity of muscle, hepatic and renal succinate dehydrogenase, and hepatic mitochondrial succinate cytochrome c reductase, whereas Pb exposure had no influence on these enzymes. There was no synergistic effect of the two factors on the activity of the enzymes. However, feeding of a Fe-deficient diet during Pb exposure enhanced the accumulation of Pb in soft tissues and flat bones. The hepatic copper and zinc levels were lowered upon either feeding a Fe-deficient diet or Pb exposure. However, the synergistic effect of the two factors was evident in hepatic Cu, but not in hepatic Zn. The feeding of a Fe-deficient diet decreased liver, kidney, and spleen levels of Fe, whereas Pb exposure decreased kidney and spleen Fe. The synergistic influence of the two factors could be observed only in liver and kidney.

Influence of methionine supplementation in chelation of lead in rats.

The influence of methionine supplementation on the efficacy of common antidotes to lead poisoning, calcium disodium ethylenediaminetetraacetate (CaNa2EDTA) and D-penicillamine (DPA), was investigated in rats. The animals were given lead acetate (0.1% in drinking water) for 12 weeks and thereafter treated with CaNa2EDTA. DPA (0.3 mmol/kg, intraperitoneally), DL-methionine (1.34 mmol/kg, intragastrically), or the combination of a chelating agent and methionine for 3 days. While chelating agents enhanced the urinary excretion of Pb, methionine increased the fecal excretion of Pb significantly. Treatment with the combination of a chelating agent and methionine did not potentiate the effect of each antidote. However, methionine supplementation increased the efficacy of both chelating agents in reducing the hepatic and renal Pb burden but not the blood Pb level. The Pb-induced inhibition of blood delta-aminolevulinic acid dehydratase activity and the increase in urinary excretion of delta-aminolevulinic acid were reversed to a certain extent by CaNa2EDTA, DPA, and methionine but the combination did not improve their individual performances. The beneficial effects of methionine may be attributed to its ability to increase the bioavailability of glutathione (GSH), useful in chelating Pb and counter-acting the toxic effects, as evidenced by restoration of the Pb-induced decrease in hepatic GSH level by treatment with methionine. Methionine may be useful as a supportive therapy in chelation of Pb.

The lead-chelating effects of substituted dithiocarbamates.

The effectiveness of certain substituted dithiocarbamates in mobilizing lead from preexposed rats was investigated. The animals received 10 mg Pb/kg/day, intragastrically, for 8 weeks and were treated thereafter with 400 mumol/kg, intraperitoneally, of morpholine dithiocarbamate, tetraammonium ethylenediamine diacetic acid dithiocarbamate (EDDTC), ammonium diethanolamine dithiocarbamate (ADDTC), sodium diethyldithiocarbamate, N-benzyl-D-glucamine dithiocarbamate (NBGDTC), or dimercaptosuccinic acid, daily for 5 days. All the chelating agents were effective in lowering the hepatic and renal burden of Pb. ADDTC, EDDTC, and NBGDTC were also able to lower the long bone Pb content. The lowering of Pb burden had no relationship to restoration of Pb-induced hematopoietic alterations. The relatively lower lipophilicity of substituted dithiocarbamates, owing to the presence of hydrophilic groups, seems to be advantageous in preventing passage of metal chelate into the brain. None of the substituted dithiocarbamates caused excessive excretion of urinary Cu and Zn. ADDTC and EDDTC appear to be promising in the management of Pb poisoning.

Occupational lead poisoning among silver jewellery workers.

Seven male silver jewellery workers aged between 25 to 70 years complained of acute abdominal colic, sweet metallic taste, constipation and anorexia. Clinical, hematological examinations and urinalysis confirmed lead poisoning. Oral therapy with D-Penicillamine for seven days led to significant improvement in patients.

Chelation in metal intoxication. XX: Effect of pre-treatment with chelators on the distribution of mercury.

The effect of pre-treatment with sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), sodium diethyldithiocarbamate (DDC) and calcium trisodium diethylenetriaminepentaacetate (DTPA) on the fate of injected mercuric chloride in rats was investigated. DMPS was the most effective chelator in reducing the uptake of Hg (203) in tissues and was the only chelator to enhance the urinary excretion of Hg (203). The results suggest affinity of Hg towards sulfur moiety and that the protective effects of pre-treatment are also shared by non-steroidal thiol chelators.

Chelation in metal intoxication. XXXVI: Effect of substituted piperazine dithiocarbamates in lead-exposed rats.

Chelation is most acceptable means of managing heavy metal poisoning. Piperazine hexahydrate dithiocarbamate (PHD), N-methyl piperazine dithiocarbamate (MPD), N-3-chloro-phenyl piperazine dithiocarbamate (CPD), and N-benzyl piperazine dithiocarbamate (BPD) were investigated for their efficacies to mobilize lead and restore Pb-induced hematopoietic alterations in experimentally intoxicated rats. MPD and CPD were effective in enhancing the urinary excretion of Pb. While PHD and MPD were successful in lowering hepatic Pb, CPD, and BPD were effective in doing so from renal tissue. All the chelating agents decreased the blood level of Pb. The lowering of Pb body burden had no influence on the restoration of biochemical changes which indicates that the latter may not be directly related to the metal mobilizing potential of the chelating agents. None of the compounds caused excessive depletion of body Cu or Zn. No relationship between efficacies of the chelating agents and their structures was seen. However, MPD and CPD appeared to be promising antidotes of Pb poisoning.

Influence of thiamine and ascorbic acid supplementation on the antidotal efficacy of thiol chelators in experimental lead intoxication.

The influence of the administration of thiamine (vitamin B1), ascorbic acid (vitamin C) or their combination on the efficacy of two thiol metal chelators, viz. alpha-mercapto-beta-(2-furyl) acrylic acid (MFA) and 2,3-dimercaptosuccinic acid (DMS), in counteracting lead (Pb) toxicity was investigated in rats. Ascorbic acid or its combination with thiamine enhanced the urinary elimination of Pb, reduced the hepatic and renal burden of Pb, and reversed the Pb-induced inhibition of the activity of blood delta-aminolevulinic acid dehydratase (delta-ALA-D). All these effects were more evident in DMS- than in MFA-treated rats. The combination of MFA and DMS treatments further improved the performance of the animals in enhancing urinary Pb excretion and in reducing Pb hepatic levels.

Chelation in metal intoxication. XXVIII: Effect of thiochelators on mercury (II) toxicity: pre- and post treatment.

The effect of treatment with alpha-mercapto-beta-(2-furyl)acrylic acid (MFA), N-(N-mercaptopropionyl) glycine (MPG) and N-acetylcysteine (NAC) compared to spironolactone (SPL), a steroid, before and after 203 mercury (II) exposure, on the disposition of Hg and induction of tissue metallothionein (MT), was investigated in rats. The pretreatment with SPL, MFA and MPG enhanced faecal elimination of Hg and reduced its accumulation in liver particularly, the "heat stable fraction" resulting in lowered hepatic MT induction. Neither the renal uptake of Hg nor induction of tissue MT was affected by pre-treatment with the chelating agents; SPL and MFA causing re-distribution of Hg among the renal sub-cellular fractions. The post-Hg exposure treatment with MFA enhanced the faecal and MPG the urinary excretion of Hg. However, both the chelating agents increased the hepatic burden of Hg as reflected in the subcellular fractions and increased MT contents indicating mobilization of Hg from other tissue binding sites. The post-treatment with MPG however, depleted renal Hg as reflected by the sub-cellular distribution, without affecting renal MT levels. The results show that MFA and MPG are more promising preventive than therapeutic agents in Hg intoxication acting as metal chelators.

Chelation in metal intoxication XXX: Alpha-mercapto-beta-aryl acrylic acids as antidotes to cadmium toxicity.

alpha-Mercapto-beta-(2-furyl) acrylic acid (MFA), alpha-mercapto-beta-(2-hydroxyphenyl) acrylic acid (MHA), beta-1,2-phenylene di-alpha-mercaptoacrylic acid (1,2-PDMA) and beta-1,4-phenylene di-alpha-mercapto acrylic acid (1,4-PDMA) were compared to sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) an effective cadmium chelator, for their ability to mobilize Cd and influence the Cd induced tissue metallothionein (MT) in rats administered 109CdCl2, 72 hr earlier. MFA was almost as effective as NBG-DTC but more effective than MHA in enhancing urinary and faecal excretion of Cd, reducing tissue and blood levels of Cd and in lowering Cd induced increase in hepatic and renal MT contents. 1,2-PDMA and 1,4-PDMA were effective only in reducing the hepatic burden of Cd. The resuls do not indicate any direct relationship between the efficacy of alpha-mercapto-beta-aryl acrylic acids to decorporate body Cd and their lipophilic-hydrophilic character or number-arrangement of their sulfhydryl groups.

Influence of copper and iron on subacute cadmium intoxication in protein-malnourished rats.

Male albino rats maintained on low-protein (9%) diets were dosed intraperitoneally with 0.75 mg Cd/kg, as cadmium chloride, for 20 days. Groups of these animals were provided with diets supplemented with 40 ppm Cu, 400 ppm Fe or a combination of both during the exposure period. Hepatic and renal distribution of Cd, Zn, Cu, and Fe along with activity of acid and alkaline phosphatases and ribonuclease and glutathione content were studied. Uptake of Cd both in liver and in kidney was significant and was accompanied by increased Zn and depletion of Fe concentration. The Cu level remained unaltered. Dietary supplementation of Cu or Fe interacted effectively and influenced the metal distribution. Acid and alkaline phosphatases in both liver and kidney were inhibited by Cd exposure. However, Cu and/or Fe supplements could to a varying degree offset the Cd-induced inhibition. Cadmium exposure did not, however, elicit any effect on hepatic and renal ribonuclease activity of low-protein-fed animals. The glutathione concentration registered profound increase on Cd exposure, possibly to act as a defence mechanism.

Influence of diethyldithiocarbamate on nickel-induced hepatic metallothionein in rats.

The influence of sodium diethyldithiocarbamate (DDC) on 63nickel chloride-induced metallothionein (MT) and alterations in essential metal levels in the liver of rats was investigated. The induction of MT, Zn and Cu levels of the hepatic cytosolic "heat stable fraction" (HSF) by DDC increased with time up to 24 hr. Although MT, Zn and Cu were significantly greater at 17 hr than those at 6.5 hr after 63Ni administration, the Ni level decreased. The treatment with DDC at 6 hr, but not at 10 min, prior to 63Ni administration increased significantly the MT, Zn and Cu contents 17 hr after 63Ni administration over that caused by 63Ni alone at 17 hr., showing a synergistic effect. The induction of hepatic MT by 63Ni or DDC alone was prevented by cycloheximide but not by actinomycin D and seemed to be regulated at the protein synthesis level.

Chelation in metal intoxication. XXIX: Alpha-mercapto-beta-aryl acrylic acids as antidotes to mercury (II) toxicity.

alpha-Mercapto-beta-(2-furyl) acrylic acid (MFA), alpha-mercapto-beta-(phenyl) acrylic acid (MPA), alpha-mercapto-beta-(2-hydroxyphenyl) acrylic acid (MHA), alpha-mercapto-beta-(4-methoxyphenyl) acrylic acid (MMA), beta-1,2-phenylene di-alpha-mercapto acrylic acid (1, 2-PDMA) and beta-1, 4-phenylene di-alpha-mercapto acrylic acid (1, 4-PDMA) enhanced faecal excretion and reduced liver, spleen and blood burden of inorganic mercury when administered (0.5 m mol/kg, in two split doses) 24 hr after Hg (II) (1 mg/kg) in rats. MFA, MPA, MHA, and MMA were also effective in lowering renal Hg mainly from the cytosol, without any significant increase in urinary excretion of Hg. The results indicate that all the mono-mercapto acrylic acids including MFA were more effective than di-mercapto acrylic acids and act through the mechanism characteristic of thiol chelators, that is, mobilization of Hg as their complexes, contrary to the reported observation that MFA acts through the induction of metallothionein.

Chelation in metal intoxication. XXV: Mercaptoacrylic acids as antidotes of lead and nickel toxicity.

beta-1,2-Phenylene di-alpha-mercaptoacrylic acid (1,2-PDMA), beta-1,4-phenylene di-alpha-mercaptoacrylic acid (1,4-PDMA) and alpha-mercapto-beta-(2-hydroxyphenyl) acrylic acid (MHA) were synthesized and compared with 2,3-dimercapto-propane-1-sulfonate (DMPS) for their ability to counteract toxic effects of lead and nickel in rats. 1,2-PDMA and DMPS were most effective in enhancing the excretion of metals, restoring most of the metal induced biochemical alterations and reducing the body burden of the metals; These observations confirm that the chelating agents with two adjacent sulfhydryl groups are better than those with non-adjacent SH groups as metal antidotes. The success of MHA in mobilizing the tissue metals and increasing their urinary excretion indicates participation of the hydroxy group on the benzene nucleus besides the SH group of the MHA molecule, in chelation of the metals.