thioacetamide and Hepatitis

The geographic map of cancer prevalence differs due to environmental and dietary factors in various populations. High prevalence of a number of cancers in some regions is thought to be attributed to local dietary habits. Dorema aucheri (Bilhar) is used commonly as an herbal medicine in some regions including Iran. The aim of this study was to evaluate whether Dorema aucheri has carcinogenic effects in albino mice or not.. The Dorema aucheri leaves were extracted by Soxhlet method and were injected intraperitoneally and randomly into 28 healthy albino mice which were divided into seven groups. One was put aside as the non-injected control group. The second control group was chosen to be injected by a known carcinogen. Another group was injected by carcinogen and then, Bilhar extract. The left four groups were injected the extracts in a dose- dependent manner, increasingly in the range of 0.4 - 3.2mL/kg. Extract injections were repeated every 48- hour intervals for three times. Then, liver and serum samples were analyzed biochemically and pathologically.. The pathologic and biochemical studies showed that the injection of plant extracts caused necrosis, inflammation of the liver tissue, cell proliferation, cholestasis, and there were significant increases in release of liver enzymes [ALP, ALT (SGPT) and AST (SGOT)] and bilirubin compared to the non-injected control group. The level of liver damage was dose dependent.. Dorema aucheri has potential hepatotoxic capacities and possibly this may be related to the high prevalence of cancer in some regions of Iran.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Apiaceae; Aspartate Aminotransferases; Bilirubin; Carcinogens; Cell Proliferation; Chemical and Drug Induced Liver Injury; Cholestasis; Hepatitis; Injections, Intraperitoneal; Liver; Mice; Necrosis; Plant Leaves; Plant Preparations; Thioacetamide

Thioacetamide is widely used in industry and is known to be one of the most potent hepatotoxicants in experimental animals. We investigated the involvement of flavin-containing monooxygenase (FMO)-dependent hepatic-neutrophil activation and the release of proinflammatory mediators in thioacetamide-induced hepatic injury in rats. Thioacetamide (100 mg/kg, intraperitoneally) increased, within 12 h, hepatic serum aspartate transferase and alanine transferase levels, tumor necrosis factor-α production, interleukin-1β and nitrite levels, and myeloperoxidase activity. Rabbit anti-neutrophil serum markedly inhibited all thioacetamide-altered parameters. In addition, FMO-competitive inhibitor methimazole reduced thioacetamide-induced myeloperoxidase activity, hepatic tumor necrosis factor-α, interleukin-1β, nitrite, inducible nitric oxide synthase, and hepatic damage in thioacetamide-treated rats. Thus, we conclude that FMO-dependent hepatic neutrophil activation initiates the release of proinflammatory mediators in thioacetamide-treated rats.

Topics: Animals; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Hepatitis; Male; Neutrophil Activation; Oxygenases; Rabbits; Rats; Rats, Wistar; Thioacetamide

The Gas6/Axl pathway has been increasingly implicated in regeneration and tissue repair and, recently, in the control of innate immunity. In liver, we have demonstrated that Gas6 and its receptor Axl are expressed in macrophages, progenitor cells, and myofibroblasts and that Gas6 deficiency reduced inflammation and myofibroblast activation, causing delayed liver repair in response to acute injury. All these data suggest a role of Gas6/Axl signaling in pathogenesis of chronic liver diseases. In the present study, we address the role of Gas6 in steatohepatitis and progression to liver fibrosis using Gas6-deficient mice fed a choline-deficient ethionine-supplemented diet (CDE) or receiving a chronic carbon tetrachloride (CCl(4)) treatment. Gas6 deficiency attenuated hepatic steatosis by limiting CDE-induced downregulation of genes involved in β-oxidation observed in wild-type animals. Moreover, Gas6-deficient mice displayed reduction of hepatic inflammation, revealed by limited F4/80-positive macrophage infiltration, decreased expression of IL-1β, TNF-α, lymphotoxin-β, and monocyte chemotactic protein-1, and attenuated hepatic progenitor cell response to CDE diet. Gas6 deficiency reduced CDE-induced fibrogenesis and hepatic myofibroblast activation and decreased expression of TGF-β and collagen 1 mRNAs. After chronic CCl(4) injury, Gas6-deficient mice also exhibited reduced liver fibrosis as a consequence of defective macrophage recruitment compared with wild-type animals. We conclude that improvement of steatohepatitis and fibrosis in Gas6(-/-) mice is linked to an inhibition of the inflammatory response that controls lipid metabolism and myofibroblast activation. This study highlights the deleterious effect of Gas6 in the progression of steatosis to steatohepatitis and fibrosis.

Topics: Animals; Axl Receptor Tyrosine Kinase; Carbon Tetrachloride; Cell Proliferation; Choline Deficiency; Disease Progression; Ethionine; Fatty Liver; Gene Expression Regulation; Hepatitis; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Lipid Metabolism; Liver; Liver Cirrhosis, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Stem Cells; Thioacetamide; Time Factors

Steatohepatitis has recently been increasing as a cofactor influencing the progression of fibrosis, cirrhosis, adenoma and carcinoma in liver; however, the mechanisms by which it contributes to liver injury remain uncertain. We induced steatohepatitis in zebrafish embryos using thioacetamide (TAA). TUNEL assay revealed significant increasing of apoptosis in liver after 5 days post fertilization and the increasing of apoptosis was observed to be associated with the up-regulation of apoptotic genes such as, bad, bax, P-38a, caspase-3 and 8, and JNK-1. Histological sections by oil red O stain showed the accumulation of fatty droplets which causes the pushing of the nucleus towards one side. Up-regulation of steatosis markers such as, ACC, adiponectin, PTL, CEBP- alpha and beta, SREBP-1 was also observed. Furthermore, the elevation of glutathione peroxidase in TAA treated embryos indicated that TAA induces lipid peroxidation which leads to causes liver damage. Zebrafish has already been considered as a good human disease model and in this context; TAA-treated zebrafish may serve as a good animal model to study the molecular pathogenesis of steatohepatitis. Moreover, non-availability of specific drugs to prevent steatohepatitis, this animal model may serve as a powerful preclinical platform to study the therapeutic strategies and for evaluating chemoprevention strategies for this disease.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Embryo, Nonmammalian; Fat Necrosis; Hepatitis; Thioacetamide; Up-Regulation; Zebrafish

Nonalcoholic steatohepatitis is most often attributed to the effects of obesity, hyperlipidemia, diabetes mellitus and drugs. It is still unknown whether livers with steatohepatitis are more vulnerable to toxic damage.. To determine the effect of the hepatotoxicant thioacetamide in a rat nutritional model of hepatic steatohepatitis.. Fatty liver was induced in rats by placing them on a methionine-choline deficient diet for one month. Thioacetamide was administered by 3 consecutive intraperitoneal injections (300 mg/kg) at 24 h intervals.. Following treatment with thioacetamide, the elevated serum levels of liver enzymes and blood ammonia, liver necrotic inflammation and the survival rate after 48 h were not different between rats with normal or fatty liver. However, those parameters were significantly worse when fatty liver regressed after return to normal diet for one month (p < 0.01). Western blot analysis of hepatic extracts revealed no difference in cytochrome P4502E1 levels between fatty livers and fatty livers after regression, suggesting that the enhanced hepatotoxicity after regression of fatty liver could not be attributed to increased cytochrome P4502E1.. In a nutritional model of steatohepatitis, rats with fatty liver were not more vulnerable than normal rats to liver damage induced by thioacetamide. However, liver damage was significantly more severe in rats with fatty livers after one month regression of steatosis.

Topics: Animals; Choline; Cytochrome P-450 CYP2E1; Fatty Liver; Hepatitis; Liver; Male; Methionine; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Thioacetamide

It is known that lidocaine is rapidly metabolized by the hepatic cytochrome P-450 system to form monoethylglycinexylidide (MEGX), its primary metabolite. We analyzed serum MEGX levels experimentally and clinically by fluorescent polarization immunoassay to reassess preoperative liver microsome functions.. Liver cirrhosis was produced in rats by intra-abdominal injection of thioacetamide. MEGX, indocyanine green test (ICG), and liver biochemical variables were measured periodically. Then, survival rates were assessed after the rats received a 70% hepatectomy.. MEGX levels were measured in various human patients with chronic hepatitis or liver cirrhosis who underwent hepatectomy. Serum MEGX levels significantly dropped and ICG levels significantly rose with macroscopic and histologic progression of liver cirrhosis in rats. The MEGX levels correlated closely with albumin levels and ICG. Preoperative MEGX and ICG levels of the mortal group of rats differed significantly from those of the survival group with 70% hepatectomy. Furthermore, 100% of the rats with MEGX levels above 40 ng/ml and ICG levels below 1.0%. In the clinical study, MEGX levels were significantly lower in patients with chronic hepatitis or liver cirrhosis than in healthy volunteers and correlated significantly with liver function tests such as albumin, Fischer's ratio, prothrombin time, hepaplastin and ICG. A significant difference was found in MEGX levels between patients receiving lobectomy and those receiving subsegmentectomy or partial hepatectomy. All patients tolerated their operations. Our data indicate that the MEGX test combined with ICG test and Child-Pugh classification is a better predictor of residual liver reserve capacity, and the analysis of hepatic MEGX formation might prove useful for rapid and reliable assessment liver function and choice of surgical treatment.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bilirubin; Disease Models, Animal; Hepatectomy; Hepatitis; Hepatitis C, Chronic; Humans; Indicators and Reagents; Indocyanine Green; Lidocaine; Liver; Liver Cirrhosis; Liver Cirrhosis, Experimental; Liver Function Tests; Male; Organic Chemicals; Prothrombin Time; Rats; Rats, Wistar; Regression Analysis; Serum Albumin; Thioacetamide

Topics: Agar; Animals; Biopsy; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Electrophoresis; Gels; Hepatitis; Histocytochemistry; Humans; Liver Cirrhosis; Liver Diseases; Proteins; Rabbits; Rats; Thioacetamide

Topics: Amides; Chemical and Drug Induced Liver Injury; Copper; Hepatitis; Histocytochemistry; Pathology; Pharmacology; Rats; Research; Sulfhydryl Compounds; Thioacetamide; Toxicology

Topics: Amides; Bilirubin; Blood Chemical Analysis; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Hepatitis; Hepatitis A; Isocitrate Dehydrogenase; Necrosis; Ouabain; Pathology; Pharmacology; Promethazine; Pyruvates; Rats; Research; Sulfhydryl Compounds; Thioacetamide; Toxicology; Transaminases

Topics: Amides; Carbon Isotopes; Chemical and Drug Induced Liver Injury; Electrons; Hepatitis; Hepatocytes; Leucine; Liver; Microscopy; Microscopy, Electron; Pharmacology; Proteins; Rats; Research; Ribosomes; RNA; Serum Albumin; Sulfhydryl Compounds; Thioacetamide; Toxicology

Topics: Chemical and Drug Induced Liver Injury; Cytoplasm; Dactinomycin; Hepatitis; Liver Regeneration; Rats; Thioacetamide; Toxicology

Topics: Amides; Antifungal Agents; Chemical and Drug Induced Liver Injury; Hepatitis; Liver Cirrhosis; Rats; Research; Sulfhydryl Compounds; Thioacetamide; Toxicology

Topics: Amides; Autoradiography; Cell Nucleus; Chemical and Drug Induced Liver Injury; Cytoplasm; DNA; Hepatitis; Liver; Rats; Research; RNA; Sulfhydryl Compounds; Thioacetamide; Toxicology; Tritium

Topics: Amides; Cell Nucleolus; Cell Nucleus; Chemical and Drug Induced Liver Injury; Hepatitis; Liver; Liver Cirrhosis; Pathology; Pharmacology; Rats; Research; Sulfhydryl Compounds; Thioacetamide; Toxicology

Topics: Amides; Animals; Chemical and Drug Induced Liver Injury; Hepatitis; Hepatitis A; Magnesium; Rats; Sulfhydryl Compounds; Thioacetamide; Thiosulfates

Topics: Amides; Cell Nucleolus; Cell Nucleus; Chemical and Drug Induced Liver Injury; Hepatitis; Hepatocytes; Liver; Pathology; Research; Sulfhydryl Compounds; Thioacetamide; Toxicology