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Response of arsenic-induced oxidative stress, DNA damage, and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats

  • S. Bhadauria
  • S. J. S. Flora
Article

Abstract

Arsenic and its compounds cause adverse health effects in humans. Current treatment employs administration of thiol chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), which facilitate its excretion from the body. However, these chelating agents are compromised by number of limitations due to their lipophobic nature, particularly in case of chronic poisoning. Combination therapy is a new approach to ensure enhanced removal of metal from the body, reduced doses of potentially toxic chelators, and no redistribution of metal from one organ to another, following chronic metal exposure. The present study attempts to investigate dose-related effects of two thiol chelators, DMSA and one of its new analogues, monoisoamyl dimercaptosuccinic acid (MiADMSA), when administered in combination with the aim of achieving normalization of altered biochemical parameters suggestive of oxidative stress and depletion of inorganic arsenic following chronic arsenic exposure. Twenty-five adult male Wistar rats were given 25 ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 0.3 mmol/kg (orally) when administered individually or 0.15 mmol/kg and 0.3 mmol/kg (once daily for 5 consecutive days), respectively, when administered in combination. Arsenic exposure led to the inhibition of blood δ-aminolevulinic acid dehydratase (ALAD) activity and depletion of glutathione (GSH) level. These changes were accompanied by significant depletion of hemoglobin, RBC and Hct as well as blood superoxide dismutase (SOD) acitivity. There was an increase in hepatic and renal levels of thiobarbituric acid-reactive substances, while GSH:GSSG ratio decreased significantly, accompanied by a significant increase in metallothionein (MT) in hepatocytes. DNA damage based on denaturing polyacrylamide gel electrophoresis revealed significant loss in the integrity of DNA extracted from the liver of arsenic-exposed rats compared to that of normal animals. These changes were accompanied by a significant elevation in blood and soft-tissue arsenic concentration. Co-administration of DMSA and MiADMSA at lower dose (0.15 mmol/kg) was most effective not only in reducing arsenic-induced oxidative stress but also in depleting arsenic from blood and soft tissues compared to other treatments. This combination was also able to repair DNA damage caused following arsenic exposure. We thus recommend combined administration of DMSA and MiADMSA for achieving optimum effects of chelation therapy.

Keywords

arsenic toxicity biochemical alteration oxidative stress DNA damage chelation therapy combination therapy arsenic mobilization 

Abbreviations

ALAD

δ-aminolevulinic acid dehydratase

DMSA

meso-2,3-dimercaptosuccinic acid

DMPS

sodium 2,3-dimercaptopropane 1-sulfonate

GSH

glutathione (reduced form)

GSSG

glutathione (oxidized form)

Hb

hemoglobin

Hct

hematocrit

MCH

mean cell hemoglobin

MCHC

mean cell hemoglobin concentration

MCV

mean cell volume

MiADMSA

monoisoamyl dimercaptosuccinic acid

MT

metallothionein

RBC

red blood cells

SOD

superoxide dismutase

TBARS

thiobarbituric acid reactive substances

WBC

white blood cells

ALT

alanine aminotransferase

AST

aspartate aminotransferase

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Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Defence Research and Development EstablishmentGwaliorIndia
  2. 2.Division of Pharmacology and ToxicologyDefence Research and Development EstablishmentGwaliorIndia

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