Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats.
Chronic arsenic toxicity is a widespread problem, not only in India and Bangladesh but also in various other regions of the world. Exposure to arsenic may occur from natural or industrial sources. The treatment that is in use at present 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 with number of limitations due to their lipophobic nature, particularly for their use in cases of chronic poisoning. During chronic exposure, arsenic gains access into the cell and it becomes mandatory for a drug to cross cell membrane to chelate intracellular arsenic. To address this problem, analogs of DMSA having lipophilic character, were examined against chronic arsenic poisoning in experimental animals. In the present study, therapeutic efficacy of meso 2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), monoisoamyl DMSA (MiADMSA) were compared in terms of reducing arsenic burden, as well as recovery in the altered biochemical variables particularly suggestive of oxidative stress. Adult male Wistar rats were given 100-ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 50 mg/Kg (orally) once daily for 5 consecutive days. Arsenic exposure resulted in marked elevation in reactive oxygen species (ROS) in blood, inhibition of ALAD activity and depletion of GSH. These changes were accompanied by significant decline in blood hemoglobin level. MiADMSA was the most effective chelator in reducing ROS in red blood cells, and in restoring blood ALAD compared to two other chelators. Brain superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased, while ROS and TBARS increased significantly following arsenic exposure. There was a significant increase in the activity of glutathione-S-transferase (GST) with a corresponding decline in its substrate i.e. glutathione. Among all the three chelators, MiADMSA showed maximum reduction in the level of ROS in brain. Additionally, administration of MiADMSA was most effective in counteracting arsenic induced inhibition in brain ALAD, SOD and GPx activity. Based on these results and in particular higher metal decorporation from blood and brain, we suggest MiADMSA to be a potential drug of choice for the treatment of chronic arsenic poisoning. However, further studies are required for the choice of appropriate dose, duration of treatment and possible effects on other major organs.
Flora
Swaran J S
SJ
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, India. sjsflora@hotmail.com
Bhadauria
Smrati
S
Pant
Satish C
SC
Dhaked
Ram K
RK
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D001151:Arsenic / Q000378:metabolism / Q000633:toxicity*; D020261:Arsenic Poisoning / Q000188:drug therapy*; D002614:Chelating Agents / Q000378:metabolism / Q000627:therapeutic use*; D004249:DNA Damage / Q000187:drug effects; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D000623:Porphobilinogen Synthase / Q000097:blood / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000097:blood; D004113:Succimer / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014494:Unithiol / Q000378:metabolism / Q000627:therapeutic use
D002614:Chelating Agents; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D014494:Unithiol; C091888:monoisoamyl-2,3-dimercaptosuccinate; D004113:Succimer; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000624:5-Aminolevulinate Synthetase; D005982:Glutathione Transferase; D000623:Porphobilinogen Synthase; D005978:Glutathione; D001151:Arsenic