Therapeutic potential of monoisoamyl and monomethyl esters of meso 2,3-dimercaptosuccinic acid in gallium arsenide intoxicated rats.
The dose dependent effects of monoisoamyl and monomethyl esters of meso 2,3-dimercaptosuccinic acid (DMSA) (0.1, 0.3 and 0.5 mmol kg(-1), intraperitoneally (i.p.) once daily for 5 days) to offset the characteristic biochemical, immunological, oxidative stress consequences and DNA damage (based on DNA fragmentation and comet assay) following sub-chronic administration of gallium arsenide and the mobilization of gallium and arsenic were examined. The effects of these chelators alone in normal animals too were examined on above-mentioned variables. Male Wistar rats were exposed to 10 mg kg(-1), GaAs, orally once daily for 12 weeks and were administered DMSA or two of its monoesters (monoisoamyl or monomethyl) for 5 consecutive days. DMSA was used as a positive control. DMSA and its derivatives, when given alone, generally have no adverse effects on various parameters. After 5 days of chelation therapy in GaAs pre-exposed rats, MiADMSA was most effective in the reduction of inhibited blood delta-aminolevulinic acid dehydratase (ALAD) activity and zinc protoporphyrin level while, all three chelators effectively reduced urinary ALA excretion, compared to GaAs alone exposed rats. MiADMSA was also effective, particularly at a dose of 0.3 mmol kg(-1), in enhancing the inhibited hepatic transaminase activities. Parameters indicative of oxidative stress responded less favorably to the chelation therapy, however, three chelators significantly restored the altered immunological variables. MiADMSA was relatively more effective than the other two chelators. GaAs produced significant DNA damage in the liver and kidneys and the chelation treatment had moderate but significant influence in reducing DNA damage. All three chelators significantly reduced arsenic concentration and, however, MiADMSA was more effective than the other two chelators in depleting arsenic concentration from blood and other soft tissues. A dose of 0.3 mmol kg(-1) was found to be relatively better than the other two doses examined. Gallium contents of blood and soft tissues remained uninfluenced by the chelation therapy. Significant loss of copper after MiADMSA administration, however, is of concern and requires further exploration. Additionally, further studies are required for the choice of appropriate dose, duration of treatment and possible toxic/side effects. Keeping in view the promising role of MiADMSA in the treatment of GaAs poisoning, these data will be needed for the registration of this chelating agent as licensed drug for the treatment of gallium arsenide intoxication.
Flora
Swaran J S
SJ
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India. sjsflora@hotmail.com
Mehta
Ashish
A
Rao
P V Lakshmana
PV
Kannan
Gurusamy M
GM
Bhaskar
A S B
AS
Dube
Shashi N
SN
Pant
Bhagwat P
BP
D000622:Aminolevulinic Acid / Q000097:blood; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000627:therapeutic use*; D020261:Arsenic Poisoning / Q000188:drug therapy* / Q000378:metabolism; D001152:Arsenicals / Q000097:blood; D015415:Biomarkers / Q000032:analysis; D002614:Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015913:Chelation Therapy; D020552:Comet Assay; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005708:Gallium / Q000097:blood / Q000506:poisoning*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011524:Protoporphyrins / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D016896:Treatment Outcome
D000931:Antidotes; D001152:Arsenicals; D015415:Biomarkers; D002614:Chelating Agents; D011524:Protoporphyrins; C017803:zinc protoporphyrin; C043055:gallium arsenide; C071157:dimercaptosuccinic acid monomethyl ester; D000622:Aminolevulinic Acid; C091888:monoisoamyl-2,3-dimercaptosuccinate; D005708:Gallium; D004113:Succimer