Devendra N. Kachru

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 δ-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 δ-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.

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 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: 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.

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 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.

Effect of manganese on certain enzymes and constituents of blood and serum in rabbits. I

Abstract Glutathione, glutathione reductase, urea, and manganese in blood; glutathione peroxidase and glucose-6-phosphate dehydrogenese in erythrocytes; total and free cholesterol in serum; and copper, manganese, and zinc in plasma were estimated in rabbits administered 0.30 mmole Mn2+/kg orally for 6 months in order to find a suitable biological indicator of early manganese poisoning. Significant increases in blood manganese, serum total cholesterol, and plasma copper were observed throughout the period of investigation while either transient or no alterations were found in other parameters.