ABSTRACT
The effect of meso 2,3-dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA (MiADMSA) on gallium arsenide (GaAs) induced liver damage was studied. The oral feeding rat model was used in this study. The animals were exposed to 10 mg/kg GaAs, orally, once daily, 5 days a week for 24 weeks and treated thereafter with single oral daily dose of either 0.3 mmol/kg DMSA or MiADMSA for two course of 5 days treatment. The animals were sacrificed thereafter. Lipid peroxidation was assessed by measuring liver thiobarbituric acid reactive substance (TBARS). Liver damage was assessed by number of biochemical variables and by light microscopy. The activity of superoxide dismutase (SOD) and delta-aminolevulinic acid dehydratase (ALAD) beside reduced glutathione (GSH) concentration was measured in blood. Exposure to GaAs produced a significant reduction in GSH while, increased the oxidized glutathione (GSSG) concentration. Hepatic glutathione peroxidase (GPx) and catalase activity increased significantly while level of serum transaminase increased moderately. Gallium arsenide exposure also produced marked hepatic histopathological lesions. Overall, treatment with MiADMSA proved to be better than DMSA in the mobilization of arsenic and in the turnover of some of the above mentioned GaAs sensitive biochemical alterations. Histopathological lesions also, responded more favorably to chelation treatment with MiADMSA than DMSA.
Subject(s)
Arsenicals/antagonists & inhibitors , Chelating Agents/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Gallium/antagonists & inhibitors , Gallium/toxicity , Succimer/analogs & derivatives , Succimer/pharmacology , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Catalase/metabolism , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/pathology , Glutathione/blood , Glutathione Peroxidase/metabolism , Lipid Peroxidation/drug effects , Liver Function Tests , Male , Metals/metabolism , Oxidation-Reduction , Oxidative Stress/drug effects , Porphobilinogen Synthase/blood , Rats , Superoxide Dismutase/metabolismABSTRACT
The hepatotoxins and neurotoxins produced by bloom-forming cyanobacteria have been the cause of human and animal health hazards and even death. The most common cyanobacterial neurotoxin is anatoxin-a, and intoxications by these toxins can be fatal through muscular paralysis causing respiratory arrest. We report here anatoxin-a-induced apoptosis in two non-neuronal cells, viz. cultured rat thymocytes and African green monkey kidney cells (Vero). Anatoxin-containing cell-free extracts (ACE) from Anabena flosaquae and purified anatoxin-a were used in the study. The toxin-induced cytotoxicity was characterized by loss of viability, lactate dehydrogenase leakage, loss of mitochondrial function, and DNA fragmentation. The toxin-induced apoptosis was characterized by plasma membrane blebbing, condensed chromatin, nuclear fragmentation and formation of apoptotic bodies. Toxin-treated thymocytes showed typical internucleosomal DNA fragmentation in agarose gel electrophoresis. Ultrastructure studies confirmed the apoptotic morphology in thymocytes. ACE and anatoxin-a showed caspase-3 activation, and pretreatment with the caspase-3-specific tetrapeptide inhibitor, acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO) abolished the DNA fragmentation and reduced the incidence of apoptotic cells. The thymocytes also showed dose- and time-dependent toxin-induced generation of reactive oxygen species. The study demonstrates that anatoxin-induced apoptosis is possibly mediated by generation of reactive oxygen species and caspase activation.
