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 |
| |
Authors: | S Bhadauria S J S Flora |
| |
Institution: | (1) Defence Research and Development Establishment, Gwalior, India;(2) Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior, 474 002, India |
| |
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 |
本文献已被 PubMed SpringerLink 等数据库收录! |
|