dinoprost and Chemical-and-Drug-Induced-Liver-Injury

Hepatic injury through carbon tetrachloride (CCl(4)) induced lipid peroxidation is well known and has been extensively used in the experimental models to understand the cellular mechanisms behind oxidative damage and further to evaluate the therapeutic potential of drugs and dietary antioxidants. Many of these methods that have often been used to study free-radical induced lipid peroxidation suffer methodological discrepancies when considering the measurements in vivo. Recent discovery of isoprostanes, non-enzymatically derived prostaglandin F(2)-like compounds, unfolded a new era of determination of oxidant stress in vivo. Cyclooxygenase (COX) catalysed prostaglandins formation from arachidonic acid and their involvement in inflammation is well known. This review mainly focuses on the formation of non-enzymatically and enzymatically catalysed eicosanoids, namely the isoprostanes and prostaglandin F(2alpha) (PGF(2alpha)), following CCl(4) treatment in animals and their regulation by antioxidants. Both eicosanoids are increased dramatically in the peripheral plasma, urine and/or liver tissues but with diverse kinetics of formation, release and excretion pattern. Free radical and COX-mediated oxidation of arachidonic acid products are intimately associated with experimental hepatotoxicity. Studies suggest that there is a link between initial involvement of oxidative stress and subsequent induction of the COX mediated inflammatory process, which may have an eminent role in the pathogenesis of liver diseases. Antioxidant nutrients have been shown to affect both the formation of isoprostanes and prostaglandin metabolite but the therapeutic values and exact mechanisms of action remain unclear.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Dinoprost; Humans; Isoprostanes; Lipid Peroxidation; Lipid Peroxides; Liver Diseases; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Reactive Oxygen Species

Topics: Animals; Arachidonic Acids; Bile; Chemical and Drug Induced Liver Injury; Cholelithiasis; Dinoprost; Dinoprostone; Gallbladder; Humans; Leukotrienes; Liver; Prostaglandins; Thromboxane A2

Paracetamol was shown to induce hepatotoxicity or more severe fatal acute hepatic damage. Agomelatine, commonly known as melatonin receptor agonist, is a new antidepressant, which resynchronizes circadian rhythms with subjective and objective improvements in sleep quality and architecture, as melatonin does. In the present study, it was aimed to evaluate the hepatoprotective activity of agomelatine on paracetamol-induced hepatotoxicity and to understand the relationship between the hepatoprotective mechanism of agomelatine and antioxidant system and proinflammatory cytokines. A total of 42 rats were divided into 7 groups as each composed of 6 rats: (1) intact, (2) 40 mg/kg agomelatine, (3) 140 mg/kg N-acetylcysteine (NAC), (4) 2 g/kg paracetamol, (5) 2 g/kg paracetamol + 140 mg/kg NAC, (6) 2 g/kg paracetamol + 20 mg/kg agomelatine, and (7) 2 g/kg paracetamol + 40 mg/kg agomelatine groups. Paracetamol-induced hepatotoxicity was applied and liver and blood samples were analyzed histopathologically and biochemically. There were statistically significant increases in the activities of aspartate aminotransferase, alanine aminotransferase, levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and 8-iso-prostane, and decreases in the activity of superoxide dismutase and level of glutathione in the group treated with paracetamol. Administration of agomelatine and NAC separately reversed these changes significantly. In conclusion, agomelatine administration protects liver cells from paracetamol-induced hepatotoxicity via antioxidant activity and reduced proinflammatory cytokines, such as TNF-α and IL-6.

Topics: Acetamides; Acetaminophen; Alanine Transaminase; Animals; Antidepressive Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Dinoprost; Glutathione; Interleukin-6; Liver; Male; Protective Agents; Rats; Rats, Wistar; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Lycopene is a carotenoid found in tomato, watermelon, pink grapefruit, and guava in high concentration. Dietary intake of lycopene has been proposed to inversely correlate with the risk of cancer. It has also been reported to provide protection against cellular damage caused by reactive oxygen species, which makes it worthwhile to study the effect of lycopene on liver damage in rat model.. In this study, we report the effect of lycopene on 7,12-dimethylbenz[a]-anthracene (DMBA)-induced expression of Bax, Bcl-2, caspases, and oxidative stres biomarkers in the liver.. Lycopene was administered orally at 20 mg/kg body weight for 20 weeks followed by the intraperitoneal injection of DMBA (50 mg/kg body weight) on day 1 and day 30 of the experiment. Control rats received vehicle (olive oil) or DMBA alone. Rats were sacrificed after completion of the treatment.. We observed that the levels of Bax, caspase-3, and caspase-9 decreased to 44, 67, and 43%, respectively, and Bcl-2 increased by 80% in DMBA-treated rats. Lycopene reversed the changes in the respective groups, and decreased the level of Bcl-2 to 25%, while increasing the Bax to 42% when compared to DMBA control. Lycopene increased the expression of caspase-3 (82.09%) and caspase-9 (58.96%), and attenuated the level of hepatic malondialdehyde (41%) and 8-isoprostane (40%) when compared to the respective controls. Glutathione (GSH) decreased significantly in DMBA group (15.89%), but reached the normal level in lycopene-treated animals. Hepatic lycopene concentration in treated rats was 8.2 nmol/g tissue.. The study reports that lycopene counteracts the hepatic response to DMBA by altering the expression of Bax, Bcl-2, caspases, and oxidative stress biomarkers in animal model.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Biomarkers; Blotting, Western; Carotenoids; Caspase 3; Caspase 9; Caspases; Chemical and Drug Induced Liver Injury; Cytoprotection; Dinoprost; Disease Models, Animal; Glutathione; Liver; Lycopene; Male; Malondialdehyde; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

One of the most toxic environmental pollutants known to man is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). There is growing evidence that indicates TCDD is a potent tumor promoter in rat and mouse liver, as well as in mouse skin. The mouse skin carcinogenesis model has been used extensively to assess whether a chemical or physical agent carries a carcinogenic hazard to humans and to define the mechanism involved with the carcinogenic effects. We applied the mouse skin model to ICR male mice and the results showed that following the application of DMBA, repeated dorsal application of all doses of TCDD produced no papillomas. These findings imply that the ICR male mouse is an extremely insensitive strain as a TCDD-induced two-stage mouse skin carcinogenesis model. However, severe hepatic injuries and wasting syndrome were seen in mice treated topically with TCDD. Meanwhile, serum TNF-alpha levels increased during the experimental periods. Inflammatory cell infiltration, fatty liver, and nodule formation could be observed in damaged livers. Elevated hepatic EROD activity and urinary 8-epi-PGF2alpha were also observed in mice with short-term exposure of TCDD.

Topics: Administration, Topical; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP1A1; Dinoprost; Environmental Pollutants; Immunohistochemistry; Lipid Peroxidation; Male; Mice; Mice, Inbred ICR; Polychlorinated Dibenzodioxins; Proliferating Cell Nuclear Antigen; Skin Neoplasms; Tumor Necrosis Factor-alpha

This report investigates the plasma and/or urinary levels of 8-iso-PGF2alpha, a nonenzymatic, and 15-keto-dihydro-PGF2alpha, a cyclooxygenase catalyzed oxidation product of arachidonic acid in experimental hepatotoxicity in rats. The study was undertaken to evaluate oxidative injury-induced inflammation as a consequence of cyclooxygenase induction. A significant and immediate increase of 8-iso-PGF2alpha in both plasma and urine after CCl4 administration indicates an oxidative injury during acute hepatotoxicity in rats. The inflammatory response index was determined by measuring 15-keto-dihydro-PGF2alpha levels in plasma which increased significantly 9-fold at 4 h after the administration of CCl4. The oxidative injury index, 8-iso-PGF2alpha, in both plasma and urine increased 17- and 53-fold, respectively. Six hours later the levels of 15-keto-dihydro-PGF2alpha in plasma remained high (5-fold increase) when 8-iso-PGF2alpha levels in plasma and urine elevated to 7- and 87-fold, respectively. Thus, cyclooxygenase and free radical-catalyzed oxidation of arachidonic acid are well involved during CCl4-induced hepatotoxicity. Cyclooxygenase-dependent inflammatory response through PGF2alpha formation in CCl4-induced hepatotoxicity may possibly be a secondary effect to oxidative injury and a conceivable link between inflammatory response and oxidative injury.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Dinoprost; Enzyme Activation; F2-Isoprostanes; Male; Malondialdehyde; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley

The effect of 15-Mt-PGF2 alpha on CCl4-induced injury of primary cultured hepatocytes was studied. 15-Mt-PGF2 alpha treatment (2 mg/L) significantly decreased CCl4 (10 mmol/L)-induced damages of primary cultured rat heptocytes as indicated by decreases GPT and GOT leakage and LPO production. 15-Mt-PGF2 alpha significantly promoted 3H-uridine incorporation into RNA and [3H]-thymidine incorporation into DNA of the rat hepatocytes. Cytopathology study showed that 15-Mt-PGF2 alpha attenuated damages of mitochondria, endoplasmic reticulum and ribosome caused by CCl4. 15-Mt-PGF2 alpha appeared to maintain the stability of rat hepatocytes by inhibiting lipid peroxidation. These results indicated that 15-Mt-PGF2 alpha has notable protective effect on primary cultured rat hepatocytes against CCl4-induced damage by reducing lipid peroxidation and promoting synthesis of RNA and DNA.

Topics: Animals; Carbon Tetrachloride Poisoning; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dinoprost; Female; Male; Rats; Rats, Sprague-Dawley

Experiments were made on 80 white rats to examine hemostatic and fibrinolytic properties of the liver, kidney, small intestine and skeletal muscle tissue and subcellular fractions (nuclei, mitochondria, nuclear supernatant liquid containing lysosomes, ribosomes, microsomes and with no mitochondria) during prostaglandin F2 alpha administration in the presence of upset protein metabolism induced by experimental toxic hepatitis and protein deficiency. It was shown that intravenous injection of prostaglandin F2 alpha leads to an increase in hemostatic properties and reduction of fibrinolytic activity of all the test tissues with the exception of gastric wall tissue which showed a different line of changes. Variation of hemostatic properties of whole tissues was followed by appropriate changes in hemocoagulation potential of subcellular fractions.

Topics: Animals; Blood Coagulation; Cell Nucleus; Chemical and Drug Induced Liver Injury; Dinoprost; Fibrinolysis; Intestine, Small; Kidney; Liver; Male; Mitochondria; Prostaglandins F; Protein Deficiency; Rats; Thrombelastography; Tissue Extracts