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1.
Environ Toxicol Pharmacol ; 76: 103333, 2020 May.
Article in English | MEDLINE | ID: mdl-32062414

ABSTRACT

Our previous study showed that percutaneous sulfur mustard (SM) exposure induced pulmonary toxicity, which was attenuated by DRDE-07 (S-2[2-aminoethylamino] ethyl phenyl sulphide) pretreatment. The present study aimed to evaluate the protective efficacy of DRDE-07 and its analogues viz., DRDE-30 (S-2(2-aminoethyl amino)ethyl propyl sulphide) and DRDE-35 (S-2(2-aminoethyl amino)ethyl butyl sulphide) against SM. Thirty minutes before percutaneous SM (0.8 LD50) exposure, female Swiss mice were orally gavaged with DRDE-07 and its analogues(0.2 LD50). Animals were sacrificed on day 3 and 7, BAL fluid (BALF) and lung tissue were collected for biochemical, histopathological studies. As results, DRDE-07 and its analogues were beneficial in reducing the number of BALF inflammatory cells, protein level, lactate dehydrogenase (LDH) activity, myeloperoxidase (MPO) and ß-glucuronidase activity, while content of BALF and lung reduced glutathione level (GSH) were significantly protected. The pretreatment of DRDE-07 and its analogues inhibited the recruitment of inflammatory cells into the lung. The beneficial effects of DRDE-07 and its analogues were attributed to their antioxidant and anti-inflammatory activity. Among the analogues, DRDE-30 exhibited significant beneficial effects as compared to the other two compounds. These analogues may be considered as prototype candidate molecules as there is no effective antidote for SM toxicity.


Subject(s)
Amifostine/analogs & derivatives , Inflammation/chemically induced , Lung Diseases/chemically induced , Lung Diseases/prevention & control , Mustard Gas/toxicity , Oxidative Stress/drug effects , Amifostine/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Bronchoalveolar Lavage Fluid/chemistry , Chemical Warfare Agents/toxicity , Female , Gene Expression Regulation, Enzymologic/drug effects , Inflammation/prevention & control , Lung/drug effects , Macrophages/drug effects , Malondialdehyde , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice
2.
Exp Lung Res ; 45(5-6): 135-150, 2019.
Article in English | MEDLINE | ID: mdl-31190576

ABSTRACT

Abrin, a highly toxic plant protein found in the seeds of Abrus precatorius plant. To date, there is no antidote against abrin intoxication. Abrin is toxic by all routes of exposure, but inhalation exposure is the most toxic of all routes. Present study was conducted to evaluate the acute inhalation toxicity of aerosolized abrin in BALB/c mice. Animals were exposed to 0.2 and 0.8LC50 doses of aerosolized abrin and evaluated at 1 and 3 day post toxin exposure. Bronchoalveolar fluid from lungs was used for evaluation of markers for lung injury. Abrin inhalation exposure caused rise in LDH activity, protein content, increase in ß-glucuronidase and myeloperoxidase activity. Increase in CRP activity, MMP-9 expression and recruitment of CD11b + inflammatory cells in lungs was also observed which was associated with severe inflammation and lung damage. Histopathological findings support the lung damage after abrin exposure. Our results indicate lung injury after single aerosol inhalation exposure, associated with excessive inflammation, oxidative stress, pulmonary edema followed by lung damage. These results could supplement treatment strategies and planning for therapeutic approaches against aerosolized abrin inhalation exposure.


Subject(s)
Abrin/toxicity , Inhalation Exposure/adverse effects , Lung Diseases/chemically induced , Lung/drug effects , Animals , Bronchoalveolar Lavage Fluid/chemistry , C-Reactive Protein/metabolism , CD11b Antigen/metabolism , Catalase/metabolism , Glucuronidase/metabolism , Glutathione/metabolism , L-Lactate Dehydrogenase/metabolism , Lung/enzymology , Lung/immunology , Lung Diseases/enzymology , Lung Diseases/immunology , Mice, Inbred BALB C , Neutrophil Activation , Peroxidase/metabolism
3.
Drug Chem Toxicol ; 39(2): 182-9, 2016.
Article in English | MEDLINE | ID: mdl-26247826

ABSTRACT

OBJECTIVE: The present study was planned to investigate the prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07), against topically applied SM induced pulmonary toxicity in mouse. MATERIALS AND METHODS: Animals were pretreated with S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) (249.4 mg/kg by oral gavage) 30 minutes before SM exposure. The SM (6.48 mg/kg) was applied on hair clipped dorsocaudal region (percutaneous) of the animal. The animals were sacrificed on day 1, 3, 5 and 7. The biochemical changes those were observed in the bronchoalveolar lavage (BAL) fluid and lung tissue included protein, LDH, MPO, ß-glucuronidase, MMP-2, MMP-9, activated macrophages, reduced glutathione and lipid peroxidation level. RESULTS AND DISCUSSION: Pretreatment with DRDE-07 (0.2 LD50) attenuated SM-induced changes at all time point tested. BAL fluid biochemical endpoints indicated epithelial and endothelial cell damages as evidenced by increase in BAL protein, LDH level and increased number of activated macrophages. The increased myeloperoxidase activity and ß-glucuronidase level exhibited the degranulation of neutrophils due to SM toxicity in lung. The zymogrphy analysis of BAL fluid showed a significant increase in matrix metalloproteases (MMP) activity due to inflammatory cells accumulation. CONCLUSION: Thirty minutes pretreatment with DRDE-07 decreased vascular permeability reduced the inflammation and oxidative stress, hence may be recommended as a potential prophylactic agent for SM intoxication.


Subject(s)
Amifostine/analogs & derivatives , Chemical Warfare Agents/toxicity , Lung Injury/prevention & control , Lung/drug effects , Mustard Gas/toxicity , Oxidative Stress/drug effects , Administration, Cutaneous , Administration, Oral , Amifostine/administration & dosage , Amifostine/pharmacology , Amifostine/therapeutic use , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Female , Flow Cytometry , Glucuronidase/metabolism , Lung/metabolism , Lung/pathology , Lung Injury/chemically induced , Lung Injury/pathology , Macrophage Activation/drug effects , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/immunology , Mice , Neutrophil Infiltration/drug effects , Peroxidase/metabolism
4.
Int J Inflam ; 2014: 827019, 2014.
Article in English | MEDLINE | ID: mdl-24669321

ABSTRACT

Increased levels of particulate air pollution are associated with increased respiratory and cardiovascular mortality and morbidity. Some epidemiologic and toxicological researches suggest ultrafine particles (<100 nm) to be more harmful per unit mass than larger particles. In the present study, the effect of particle size (nano and micro) of carbon black (CB) particle on viability, phagocytosis, cytokine induction, and DNA damage in human monocytes, THP-1 cells, was analysed. The cells were incubated with nanosize (~50 nm) and micron (~500 nm) size of CB particles in a concentration range of 50-800 µg/mL. The parameters like MTT assay, phagocytosis assay, ELISA, gene expression, and DNA analysis were studied. Exposure to nano- and micron-sized CB particles showed size- and concentration dependent decrease in cell viability and significant increase in proinflammatory cytokines IL-1 ß , TNF- α and IL-6 as well as chemokine IL-8 release. Gene expression study showed upregulation of monocyte chemoattractant protein-1 gene while cyclooxygenase-2 gene remained unaffected. Nano CB particles altered the phagocytic capacity of monocytes although micron CB had no significant effect. CB particles did not show any significant effect on DNA of monocytes. The investigations indicate that CB particles in nanosize exhibit higher propensity of inducing cytotoxicity, inflammation, and altered phagocytosis in human monocytes than their micron size.

5.
J Toxicol Environ Health A ; 77(4): 177-91, 2014.
Article in English | MEDLINE | ID: mdl-24555677

ABSTRACT

With the rapid development of nanomedicines, it is important to understand their potential immunotoxicity. Zinc oxide (ZnO) nanoparticles have several applications in the pharmaceutical and biomedicine industries. This study investigates the effect of particles size (nano and micro) of ZnO on viability, phagocytosis, and cytokine induction in human monocytes, THP-1 cells, a model of the innate immune system. Cells were incubated with nano (approximately 100 nm) and micro (approximately 5 µm) sized ZnO particles in a concentration range of 10-100 µg/ml. The parameters measured included the MTT assay, phagocytosis assay, enzyme-linked immunosorbent assay (ELISA), gene expression, and DNA analysis. ZnO particles significantly decreased cell viability in a size- and concentration-dependent manner associated with significant alterations in phagocytic capacity of monocytes. Exposure of THP-1 cells to both sizes of ZnO stimulated and increased release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6, as well as chemokine IL-8, and upregulated the expression of monocyte chemoattractant protein-1 and cyclooxygenase-2 genes. However, ZnO particles did not markedly affect monocytes DNA. Collectively, these results suggest higher propensity of nano ZnO particles in inducing cytotoxicity and inflammation in human monocytes regardless of micro size, and caution needs to be taken concerning their biological application.


Subject(s)
Cytokines/metabolism , Immunity, Innate/drug effects , Metal Nanoparticles/toxicity , Monocytes/drug effects , Phagocytosis/drug effects , Up-Regulation/drug effects , Zinc Oxide/pharmacology , Cell Line , Cell Survival , Chemokine CCL2/biosynthesis , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Cyclooxygenase 2/biosynthesis , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Cytokines/genetics , DNA Damage , Enzyme Induction/drug effects , Humans , Kinetics , Metal Nanoparticles/chemistry , Metal Nanoparticles/ultrastructure , Microspheres , Monocytes/immunology , Monocytes/metabolism , Mutagens/chemistry , Mutagens/pharmacology , Mutagens/toxicity , Particle Size , RNA, Messenger/metabolism , Surface Properties , Zinc Oxide/chemistry , Zinc Oxide/toxicity
6.
ISRN Toxicol ; 2013: 316075, 2013.
Article in English | MEDLINE | ID: mdl-23997968

ABSTRACT

Zinc oxide nanoparticles (ZnO-NPs) are increasingly used in sunscreens, biosensors, food additives, pigments, rubber manufacture, and electronic materials. With the wide application of ZnO-NPs, concern has been raised about its unintentional health and environmental impacts. This study investigates the toxic effects of ZnO-NPs in human lung cells. In order to assess toxicity, human lung epithelial cells (L-132) were exposed to dispersion of 50 nm ZnO-NPs at concentrations of 5, 25, 50, and 100 µ g/mL for 24 h. The toxicity was evaluated by observing changes in cell morphology, cell viability, oxidative stress parameters, DNA damage analysis, and gene expression. Exposure to 50 nm ZnO-NPs at concentrations between 5 and 100 µ g/mL decreased cell viability in a concentration-dependent manner. Morphological examination revealed cell shrinkage, nuclear condensation, and formation of apoptotic bodies. The oxidative stress parameters revealed significant depletion of GSH level and increase in ROS levels suggesting generation of oxidative stress. ZnO-NPs exposure caused DNA fragmentation demonstrating apoptotic type of cell death. ZnO-NPs increased the expression of metallothionein gene, which is considered as a biomarker in metal-induced toxicity. To summarize, ZnO-NPs cause toxicity in human lung cells possibly through oxidative stress-induced apoptosis.

7.
J Environ Biol ; 28(2 Suppl): 333-47, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17929749

ABSTRACT

Arsenic is a naturally occurring metalloid, ubiquitously present in the environment in both organic and inorganic forms. Arsenic contamination of groundwater in the West Bengal basin in India is unfolding as one of the worst natural geoenvironmental disaster to date. Chronic exposure of humans to high concentration of arsenic in drinking water is associated with skin lesions, peripheral vascular disease, hypertension, Blackfoot disease and high risk of cancer The underlying mechanism of toxicity includes the interaction with the sulphydryl groups and the generation of reactive oxygen species leading to oxidative stress. Chelation therapy with chelating agents like British Anti Lewisite (BAL), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), meso 2,3 dimercaptosuccinic acid (DMSA) etc., is considered to be the best known treatment against arsenic poisoning. The treatment with these chelating agents however is compromised with certain serious drawbacks/side effects. The studies show that supplementation of antioxidants along with a chelating agent prove to be a better treatment regimen. This review attempts to provide the readers with a comprehensive account of recent developments in the research on arsenic poisoning particularly the role of oxidative stress/free radicals in the toxic manifestation, an update about the recent strategies for the treatment with chelating agents and a possible beneficial role of antioxidants supplementation to achieve the optimum effects.


Subject(s)
Antioxidants/therapeutic use , Arsenic Poisoning/drug therapy , Chelating Agents/therapeutic use , Environmental Pollutants/poisoning , Acetylcysteine/therapeutic use , Animals , Ascorbic Acid/therapeutic use , Chelation Therapy , Dimercaprol/therapeutic use , Drug Therapy, Combination , Humans , Melatonin/therapeutic use , Oxidative Stress/drug effects , Plant Extracts/therapeutic use , Selenium/therapeutic use , Succimer/analogs & derivatives , Succimer/therapeutic use , Taurine/therapeutic use , Thioctic Acid/therapeutic use , Vitamin E/therapeutic use , Zinc/therapeutic use
8.
Cell Biol Int ; 31(1): 44-56, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17055307

ABSTRACT

Contamination of ground water by arsenic has become a cause of global public health concern. In West Bengal, India, almost 6 million people are endemically exposed to inorganic arsenic by drinking heavily contaminated groundwater through hand-pumped tube wells. No safe, effective and specific preventive or therapeutic measures for treating arsenic poisoning are available. We recently reported that some of the herbal extracts possess properties effective in reducing arsenic concentration and in restoring some of the toxic effects of arsenic in animal models. Moringa oleifera Lamarack (English: Horseradish-tree, Drumstick-tree, Hindi: Saijan, Sanskrit: Shigru) belongs to the Moringaceae family, is generally known in the developing world as a vegetable, a medicinal plant and a source of vegetable oil. The objective of the present study was to determine whether Moringa oleifera (M. oleifera) seed powder could restore arsenic induced oxidative stress and reduce body arsenic burden. Exposure to arsenic (2.5 mg/kg, intraperitoneally for 6weeks) led to a significant increase in the levels of tissue reactive oxygen species (ROS), metallothionein (MT) and thiobarbituric acid reactive substance (TBARS) which were accompanied by a decrease in the activities in the antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) in mice. Arsenic exposed mice also exhibited liver injury as reflected by reduced acid phosphatase (ACP), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) activities and altered heme synthesis pathway as shown by inhibited blood delta-aminolevulinic acid dehydratase (delta-ALAD) activity. Co-administration of M. oleifera seed powder (250 and 500 mg/kg, orally) with arsenic significantly increased the activities of SOD, catalase, GPx with elevation in reduced GSH level in tissues (liver, kidney and brain). These changes were accompanied by approximately 57%, 64% and 17% decrease in blood ROS, liver metallothionein (MT) and lipid peroxidation respectively in animal co-administered with M. oleifera and arsenic. Another interesting observation has been the reduced uptake of arsenic in soft tissues (55% in blood, 65% in liver, 54% in kidneys and 34% in brain) following administration of M. oleifera seed powder (particularly at the dose of 500 mg/kg). It can thus be concluded from the present study that concomitant administration of M. oleifera seed powder with arsenic could significantly protect animals from oxidative stress and in reducing tissue arsenic concentration. Administration of M. oleifera seed powder thus could also be beneficial during chelation therapy with a thiol chelator.


Subject(s)
Arsenic Poisoning/prevention & control , Arsenic/toxicity , Moringa oleifera , Oxidative Stress/drug effects , Powders/administration & dosage , Animals , Brain/drug effects , Enzymes/blood , Heme/biosynthesis , Kidney/drug effects , Liver/drug effects , Liver/enzymology , Male , Mice , Moringa oleifera/chemistry , Powders/chemistry , Reactive Oxygen Species/analysis , Seeds/chemistry , Treatment Outcome
9.
Article in English | MEDLINE | ID: mdl-17188940

ABSTRACT

We compared the therapeutic efficacy of captopril and a thiol chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA) either individually or in combination against arsenite induced oxidative stress and mobilization of metal in rats. Animals were exposed to 100 ppm arsenite as sodium arsenite in drinking water for six weeks followed by treatment with DMSA (50 mg/kg, orally), captopril (50 mg/kg, intraperitoneally) either alone or in combination, once daily for 5 consecutive days. Arsenite exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, glutathione and platelet levels while significantly increased the level of reactive oxygen species (in RBCs). Hepatic reduced glutathione (GSH) level showed a significant decrease while, thiobarbituric acid reactive substances (TBARS) levels increased on arsenite exposure indicating arsenite induced hepatic oxidative stress. Kidney GSH, GSSG, catalase and TBARS remained unchanged on arsenite exposure. Treatment with DMSA was effective in increasing ALAD activity while, captopril was ineffective when given alone. Captopril when co-administered with DMSA also provided no additional beneficial effect on blood ALAD activity but significant brought altered platelet counts back to the normal value. In contrast, administration of captopril alone provided significant beneficial effects on hepatic oxidative stress, and in combination with DMSA provided a more pronounced recovery in the TBARS level compared to the individual effect of DMSA and captopril. Renal biochemical variables remained insensitive to arsenite and any of the treatments. Interestingly, combined administration of captopril with DMSA had a remarkable effect in depleting total arsenic concentration from blood and soft tissues. These results lead us to conclude that captopril administration during chelation treatment had some beneficial effects particularly on the protection of inhibited blood ALAD activity, and depletion of arsenic level. The study supports our earlier conclusion that a co-administration of an antioxidant is more beneficial than monotherapy with the chelating agents, in order to achieve optimal effects of chelation in arsenite toxicity.


Subject(s)
Antidotes/pharmacology , Antioxidants/pharmacology , Arsenites/toxicity , Captopril/pharmacology , Succimer/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Arsenic/blood , Arsenic/metabolism , Arsenites/pharmacokinetics , Brain/metabolism , Copper/metabolism , Drug Interactions , Glutathione/blood , Glutathione/metabolism , Glutathione Disulfide/metabolism , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/metabolism , Male , Oxidative Stress , Porphobilinogen Synthase/blood , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Thiobarbituric Acid Reactive Substances/metabolism , Zinc/metabolism
10.
Cell Mol Biol (Noisy-le-grand) ; 50 Online Pub: OL543-51, 2004.
Article in English | MEDLINE | ID: mdl-15555419

ABSTRACT

Lead is a ubiquitous element in the environment causing oxidative burst in the exposed individuals leading to tissue damage. Antioxidants have long been known to reduce the free radical-mediated oxidative stress while, thiol chelators have been used to treat arsenic toxicity. The therapeutic efficacy of melatonin or N-acetylcysteine (NAC) was studied in the present study, both individually and in combination with a potent thiol-chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA), in reducing lead concentration in blood and other soft tissues. Their ability to restore altered haematopoietic, hepatic and other biochemical variables indicative of tissue oxidative stress in male rats was also investigated. Administration of melatonin and NAC individually, provided significant protection to lead induced disturbed antioxidant defense that may significantly compromise normal cellular function. Administration of melatonin and NAC also provided a significant protection to thiobarbituric acid reactive substances (TBARS) levels, reduced glutathione (GSH) and oxidized glutathione (GSSG) contents in tissues, suggesting their ability to act as a free radical scavenger and in protecting cells against toxic insult. NAC, a thiol containing antioxidant, has been used under several clinical conditions with few adverse side effects. It has a high toxicity threshold and its wide therapeutic window enhances its utility. The antioxidant action of NAC is due to its ability to interact with reactive oxygen species (ROS) or its ability to stimulate endogenous glutathione (GSH) synthesis. DMSA, on the other hand when given alone, provided significant recovery in restoring the altered lead sensitive biochemical indices like blood delta-aminolevulinic acid dehydratase (ALAD), urinary delta-aminolevulinic acid (ALA), beside increasing urinary lead excretion and decreasing lead concentration in blood and soft tissues. Interestingly, combined treatment of DMSA and NAC provided more pronounced efficacy in restoring altered biochemical variables and in reducing body lead burden than monotherapy with DMSA. The results thus, suggest the involvement of ROS in lead toxicity and a pronounced beneficial role of NAC in therapeutic implications of lead poisoning when co-administered with a thiol chelator (DMSA) supporting the hypothesis that cellular redox status may be significantly reversed by utilizing a thiol containing antioxidant compound. It can be concluded that, combined therapy with an antioxidant moiety and a thiol-chelating agent may be a better choice for treating plumbism.


Subject(s)
Acetylcysteine/therapeutic use , Antioxidants/therapeutic use , Chelating Agents/therapeutic use , Lead Poisoning/prevention & control , Melatonin/therapeutic use , Oxidative Stress/drug effects , Succimer/therapeutic use , Acetylcysteine/administration & dosage , Animals , Brain/drug effects , Brain Chemistry , Kidney/chemistry , Kidney/drug effects , Lead/analysis , Lead Poisoning/enzymology , Lead Poisoning/metabolism , Liver/chemistry , Liver/drug effects , Male , Melatonin/administration & dosage , Rats
11.
Hum Exp Toxicol ; 23(4): 157-66, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15171566

ABSTRACT

The present study describes the dose-dependent effect of taurine, an amino acid and a known antioxidant, either alone or in combination with meso 2,3-dimercaptosuccinic acid (DMSA) in the treatment of subchronic lead intoxication in male rats. The effects of these treatments in influencing the lead-induced alterations in haem synthesis, hepatic, renal or brain oxidative stress and lead concentration from soft tissues were investigated. Exposure to lead produced a significant inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity, reduction in glutathione (GSH) and an increase in zinc protoporphyrin (ZPP) suggesting an altered haem synthesis pathway. Only DMSA was able to increase the activity of ALAD, while both taurine and DMSA were able to significantly increase GSH level towards normal. Animals treated with taurine significantly reduced the alterations in some of the biochemical parameters indicative of oxidative stress. Thiobarbituric acid reactive substance (TBARS) levels reduced significantly in liver, kidney and red blood cells, while GSH level increased. Activity of superoxide dismutase (SOD) also showed an increase in blood and brain in animals treated with taurine. The data also provided a promising role of taurine during chelation of lead by potentiating the depletion of blood, liver and brain lead compared to DMSA alone. It can thus be concluded from the study that concomitant administration of an antioxidant could play a significant and important role in abating a number of toxic effects of lead when administered along with the thiol chelators.


Subject(s)
Antioxidants/therapeutic use , Chelating Agents/therapeutic use , Lead Poisoning/drug therapy , Succimer/therapeutic use , Taurine/therapeutic use , Aminolevulinic Acid/blood , Animals , Antioxidants/administration & dosage , Brain/enzymology , Brain/metabolism , Chelating Agents/administration & dosage , Drug Therapy, Combination , Erythrocytes/metabolism , Glutathione/metabolism , Kidney/metabolism , Lead Poisoning/metabolism , Liver/enzymology , Liver/metabolism , Male , Organometallic Compounds/poisoning , Oxidative Stress/drug effects , Protoporphyrins/metabolism , Rats , Rats, Wistar , Succimer/administration & dosage , Superoxide Dismutase/metabolism , Taurine/administration & dosage , Thiobarbituric Acid Reactive Substances/metabolism
12.
Article in English | MEDLINE | ID: mdl-12635830

ABSTRACT

The therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA), a new monoester of 2,3-dimercaptosuccinic acid on arsenic induced oxidative stress in liver and kidneys, alterations in hematopoietic system and depletion of arsenic burden was assessed, in mice. Three different doses of MiADMSA (25, 50 or 100 mg/kg) for five consecutive days were administered in chronically arsenic exposed mice (10 ppm in drinking water for six months). Oral administration of MiADMSA particularly at a dose of 50 mg/kg, produced relatively more pronounced beneficial effects on the inhibited blood delta-aminolevulinic acid dehydratase (ALAD), biochemical variables indicative of hepatic and renal oxidative stress and depletion of arsenic concentration in blood, liver and kidneys, compared with intraperitoneal administration of the drug. The treatment with MiADMSA although, produced essential metals imbalance which could be a restrictive factor for the possible therapeutic use of this compound in chronic arsenic poisoning and thus require further exploration.


Subject(s)
Arsenic Poisoning/therapy , Oxidative Stress , Succimer/analogs & derivatives , Succimer/pharmacology , Administration, Oral , Animals , Disease Models, Animal , Infusions, Parenteral , Kidney/pathology , Liver/pathology , Male , Mice , Succimer/administration & dosage
13.
J Appl Toxicol ; 22(6): 359-69, 2002.
Article in English | MEDLINE | ID: mdl-12424740

ABSTRACT

Monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a vicinal thiol chelator, is gaining recognition recently as a better chelator than meso 2,3-dimercaptosuccinic acid (DMSA) in decreasing heavy metal burden in tissues because of its lipophilic character. There is, however, little information available on the toxicological properties of this chelator after repeated administration in animals. In the present study, we investigated the dose-dependent effect of MiADMSA on various biochemical parameters suggestive of alterations in haem biosynthesis and hepatic, renal and brain oxidative stress after 21 days of repeated intraperitoneal (i.p.) or oral (p.o.) administration to rats. The concentration of essential metals in blood and soft tissues was determined along with histopathological observations of hepatic and renal tissues. The results suggest that MiADMSA administration had no effect on blood delta-aminolevulinic acid dehydratase activity. However, an increase in zinc protoporphyrin and a decrease in haemoglobin levels were noted in animals given MiADMSA i.p. A moderate increase in serum alkaline phosphatase suggested mild hepatotoxicity at the highest dose (100 mg kg(-1), i.p.). This was confirmed by histopathological examinations, which identified basophilic stippling, granulation of the cytoplasm, haemorrhage and congestion. At the highest dose, levels of hepatic thiobarbituric acid reactive substance and oxidized glutathione were increased above those of control values. Levels of hepatic reduced glutathione were decreased. Taken together, these observations point to oxidative stress. In animals administered MiADMSA i.p. there was an increase in the brain malondialdehyde levels at the two higher doses (50 and 100 mg kg(-1)). Essential metal status revealed a significant effect of MiADMSA (p.o.) in increasing blood zinc while significantly decreasing the kidney zinc level. The most significant adverse effect of MiADMSA was on copper concentration, which showed significant depletion from almost all major organs. Magnesium levels in blood decreased but increased in liver of MiADMSA-administered rats. Histopathological observations of liver and kidneys suggest few moderate lesions. It can be concluded that repeated administration of MiADMSA is compromised with some mild toxic effect, particularly the loss of copper. The effects during oral administration are comparatively less pronounced than by the i.p. route.


Subject(s)
Chelating Agents/toxicity , Succimer/analogs & derivatives , Succimer/toxicity , Administration, Oral , Animals , Brain/drug effects , Brain/metabolism , Chelating Agents/administration & dosage , Copper/blood , Dose-Response Relationship, Drug , Heme/biosynthesis , Injections, Intraperitoneal , Iron/blood , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Oxidative Stress , Rats , Rats, Wistar , Succimer/administration & dosage , Tissue Distribution , Zinc/blood
14.
Toxicol Lett ; 132(1): 9-17, 2002 Jun 07.
Article in English | MEDLINE | ID: mdl-12084615

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/metabolism
15.
Cytobios ; 104(406): 99-105, 2001.
Article in English | MEDLINE | ID: mdl-11258544

ABSTRACT

The beneficial effects of S-adenosyl-L-methionine (SAM) in potentiating the mobilization of cadmium by cadmium trisodium diethylenetriamine penta acetic acid (DTPA) from the major target organs and restoration of depleted tissue glutathione (GSH), zinc and copper concentration, were determined in cadmium-exposed mice. The results indicated a significant depletion of cadmium concentration from the blood in DTPA plus SAM treated animals compared with DTPA or SAM alone treated groups. The treatment with SAM alone was also effective in correcting the zinc and GSH concentrations. The results indicated few beneficial effects of concomitant SAM administration during chelation of cadmium with DTPA.


Subject(s)
Cadmium Poisoning/drug therapy , Cadmium/antagonists & inhibitors , Chelating Agents/administration & dosage , Pentetic Acid/administration & dosage , S-Adenosylmethionine/administration & dosage , Animals , Cadmium/pharmacokinetics , Copper/pharmacokinetics , Drug Synergism , Drug Therapy, Combination , Glutathione/pharmacokinetics , Kidney/metabolism , Liver/metabolism , Male , Mice , Spleen/metabolism , Zinc/pharmacokinetics
16.
J Toxicol Clin Toxicol ; 39(7): 675-82, 2001.
Article in English | MEDLINE | ID: mdl-11778665

ABSTRACT

OBJECTIVE: To evaluate the effects of arsenic (III) exposure on porphyrin metabolism and the central nervous system supplemented with data on the effect of hepatic and renal tissues of rats and guinea pigs. METHODS: Rats and guinea pigs were exposed to 10 or 25 ppm arsenic in drinking water for 16 weeks. RESULTS: Following chronic arsenic (III) exposure, delta-aminolevulinic acid dehydratase activity in blood showed a significant reduction as did the total cell counts (RBC and WBC) and reduced glutathione with increased urinary delta-aminolevulinic acid. Zinc protoporphyrin, a sensitive indicator of iron deficiency and impairment of heme biosynthesis, showed a significant increase in arsenic exposure. The hepatic delta-aminolevulinic acid dehydratase and delta-aminolevulinic acid synthetase activity increased in chronic arsenic (III) exposure in rats and guinea pigs. Significant changes in the steady-state level of three major neurotransmitters, dopamine, norepinephrine, and 5-hydroxytryptamine, and monoamine oxidase were observed following chronic arsenic (III) exposure. CONCLUSION: At low doses (10 and 25 ppm in drinking water), the effects of arsenic on hematopoietic indices and whole-brain neurotransmitter concentrations were more prominent in guinea pigs than in rats with some variability in the dose response.


Subject(s)
Arsenites/toxicity , Brain/drug effects , Hematopoietic System/drug effects , Sodium Compounds/toxicity , 5-Aminolevulinate Synthetase/metabolism , Aminolevulinic Acid/blood , Aminolevulinic Acid/urine , Animals , Arsenites/pharmacokinetics , Biogenic Monoamines/metabolism , Blood Cell Count , Blood Cells/drug effects , Dose-Response Relationship, Drug , Drinking , Glutathione/blood , Guinea Pigs , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/enzymology , Male , Porphobilinogen Synthase/blood , Protoporphyrins/blood , Rats , Sodium Compounds/pharmacokinetics , Water Supply
17.
Biomed Environ Sci ; 13(3): 225-32, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11198225

ABSTRACT

Sulphur mustard [bis(2-chloro ethyl) sulfide] (SM), a bifunctional alkylating agent has been frequently used as a chemical warfare agent. In the present study, the effects of sodium 2-3-dimercaptopropane sulphonic acid (DMPS) on some biochemical and histological parameters in mice, exposed to 1/4LC50 concentration of SM vapor (10.5 mg/m3) were examined over a period of seven days. Exposure of SM resulted in a significant loss of blood, hepatic and pulmonary glutathione (GSH) and an elevation of hepatic and pulmonary oxidized glutathione (GSSG). These biochemical changes were accompanied by a number of histopathological alterations. The most prominent was congestion and degeneration in viscera and obliteration of chromatin material. These biochemical and histopathological changes were less marked in animals pre-administered with DMPS followed by DMPS exposure indicating some protective value of the thiol (DMPS) against SM induced oxidative injury in mice.


Subject(s)
Mustard Gas/pharmacology , Oxidative Stress/drug effects , Unithiol/pharmacology , Animals , Female , Mice
18.
Chem Biol Interact ; 122(1): 1-13, 1999 Aug 30.
Article in English | MEDLINE | ID: mdl-10475611

ABSTRACT

The influence of selenium (6.3 and 12.6 micromol/kg, intraperitoneally) on the disposition of gallium and arsenic and a few gallium arsenide (GaAs) sensitive biochemical variables was studied in male rats. Concomitant administration of Se and GaAs (70 micromol/kg, orally, 5 days a week for 4 weeks) significantly prevented the accumulation of arsenic while, the gallium concentration reduced moderately in the soft organs. The biochemical (haematopoietic and liver) and immunological variables however, responded less favorably to selenium administration. Most of the protection was however observed with the dose of 12.6 micromol rather than at 6.3 micromol. The results thus suggest a few beneficial effects of selenium in preventing the appearance of signs of GaAs toxicity like preventing inhibition of blood delta-aminolevulinic acid dehydratase (ALAD), hepatic malondialdehyde (MDA) formation and the accumulation of gallium and arsenic concentration.


Subject(s)
Arsenic Poisoning , Arsenicals , Chemical and Drug Induced Liver Injury , Gallium/toxicity , Hematopoiesis/drug effects , Immunotoxins/toxicity , Selenium/pharmacology , Animals , Body Weight/drug effects , Injections, Intraperitoneal , Male , Organ Size/drug effects , Rats , Rats, Wistar
19.
J Appl Toxicol ; 18(5): 357-62, 1998.
Article in English | MEDLINE | ID: mdl-9804436

ABSTRACT

The concomitant administration of zinc during chelation of cadmium (Cd) with meso-2,3-dimercaptosuccinic acid (DMSA) or calcium trisodium diethylenetriamine penta-acetic acid (DTPA) was investigated in male rats subchronically exposed to Cd. The results suggest that the administration of zinc alone after cadmium exposure does not elicit any protective effects. However, when supplemented during treatment with DTPA it produced a significant turnover in the altered biochemical variables and a depletion of Cd concentration in liver and kidneys. Cadmium-induced elevated hepatic metallothionein (MT) contents remained practically unaltered on Zn-DTPA administration, but there was a significant increase in renal MT levels compared to rats administered Cd-DTPA or Cd alone.


Subject(s)
Cadmium/toxicity , Chelating Agents/therapeutic use , Zinc/therapeutic use , Animals , Cadmium/metabolism , Kidney/metabolism , Liver/metabolism , Male , Pentetic Acid/therapeutic use , Rats , Rats, Wistar , Succimer/therapeutic use
20.
Toxicol Lett ; 94(2): 103-13, 1998 Jan 31.
Article in English | MEDLINE | ID: mdl-9574807

ABSTRACT

Male albino rats were given a single oral dose of gallium arsenide (GaAs) (100, 200 or 500 mg/kg). Erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity was inhibited in all the three GaAs-exposed groups accompanied by elevated urinary excretion of ALA. A significant increase in serum aspartate aminotransferase (AST) activity, and gamma-glutamyltranspeptidase (gamma-GT) was observed. A significant increase in hepatic malondialdehyde (MDA) and a decrease in hepatic glutathione contents were also noted. Renal alkaline phosphatase activity, urinary ALA and protein excretion increased significantly on GaAs exposure. These changes were accompanied by significant alterations in almost all the immunological variables, with an increase in gallium and arsenic concentration in blood and soft tissues. While most of the above biochemical alterations were prominent at day 7 following single exposure to 200 and 500 mg/kg GaAs, most of the immunological indices altered with all the three doses and remained high even at day 21. The results suggest only a moderate effect of GaAs on renal and hepatic tissues. By contrast, immunological and haematological systems are the most vulnerable to the toxic effects of GaAs.


Subject(s)
Air Pollutants, Occupational/toxicity , Arsenic Poisoning , Gallium/toxicity , Kidney/drug effects , Liver/drug effects , Administration, Oral , Air Pollutants, Occupational/immunology , Air Pollutants, Occupational/pharmacokinetics , Alkaline Phosphatase/metabolism , Aminolevulinic Acid/urine , Animals , Antibody-Producing Cells/drug effects , Arsenicals/immunology , Arsenicals/pharmacokinetics , Aspartate Aminotransferases/blood , Dose-Response Relationship, Drug , Gallium/immunology , Gallium/pharmacokinetics , Glutathione/metabolism , Kidney/enzymology , Kidney/metabolism , Liver/enzymology , Liver/metabolism , Male , Malondialdehyde/metabolism , Porphobilinogen Synthase/antagonists & inhibitors , Porphobilinogen Synthase/blood , Rats , Rats, Wistar , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Spleen/metabolism , Time Factors , Tissue Distribution , gamma-Glutamyltransferase/blood
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