thioacetamide and Carbon-Tetrachloride-Poisoning

Sustained activation of hepatic stellate cells (HSCs) leads to hepatic fibrosis, which is characterized by excessive collagen production, and for which there is no available drug clinically. Despite tremendous progress, the cellular activities underlying HSC activation, especially the driving force in the perpetuation stage, are only partially understood. Recently, microRNA-21 (miR-21) has been found to be prevalently up-regulated during fibrogenesis in different tissues, although its detailed role needs to be further elucidated. In the present study, miR-21 expression was examined in human cirrhotic liver samples and in murine fibrotic livers induced by thioacetamide or carbon tetrachloride. A dramatic miR-21 increase was noted in activated HSCs. We further found that miR-21 maintained itself at constant high levels by using a microRNA-21/programmed cell death protein 4/activation protein-1 (miR-21/PDCD4/AP-1) feedback loop. Disrupting this loop with miR-21 antagomir or AP-1 inhibitors significantly suppressed fibrogenic activities in HSCs and ameliorated liver fibrosis. In contrast, reinforcing this loop with small interfering RNA (siRNA) against PDCD4 promoted fibrogenesis in HSCs. Further analysis indicated that the up-regulated miR-21 promoted the central transforming growth factor-β (TGF-β) signaling pathway underlying HSC activation. In summary, we suggest that the miR-21/PDCD4/AP-1 autoregulatory loop is one of the main driving forces for hepatic fibrosis progression. Targeting this aberrantly activated feedback loop may provide a new therapeutic strategy and facilitate drug discovery against hepatic fibrosis.

Topics: Adult; Aged; Animals; Apoptosis Regulatory Proteins; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Female; Hepatic Stellate Cells; Humans; Liver Cirrhosis, Experimental; Male; Mice; Mice, Inbred ICR; MicroRNAs; Middle Aged; RNA-Binding Proteins; Signal Transduction; Thioacetamide; Transcription Factor AP-1; Transforming Growth Factor beta

Depression is a highly prevalent mental disease and increasingly become a global public health problem. Recent studies have shown that the dysfunction of liver was associated with depression. However, the previous studies have not been fully explained the relationship between depression and liver injury. The present study was aimed to investigate whether chronic liver injury could induce depressive-like behavior. Chronic liver injury was induced by intraperitoneal injection of carbon (CCl

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Depression; Female; Galactosamine; Hindlimb Suspension; Hippocampus; Liver; Male; Mice; Swimming; Thioacetamide

Establishing an easy and reproducible model for hepatic fibrosis is absolutely necessary for research on liver reperfusion injury. We compared the characteristics of several hepatic cirrhosis models in terms of the degree of fibrosis, reproducibility, histologic characteristics, and success rate to achieve sufficient fibrosis. In mice & rats, we administered three different hepatotoxic drugs (thioacetamide, dimethylnitrosamine, and carbon tetrachloride [CCl4]) through two different routes (oral feeding and intraperitoneal injection). The animals fed thioacetamide exhibited little fibrosis; rather, more inflammatory cells infiltrated into periportal areas with bile duct proliferation. The livers from hosts administered dimethylnitrosamine showed greater early injury and severe inflammatory reactions in the peritoneal cavity. The liver showed a marked degree of piecemeal necrosis with limited fibrosis. The mice administered a 50% solution of CCl4 (2 mL/kg orally) tolerated the entire induction period of 12 weeks. The degree of fibrosis correlated well with the duration of induction. Livers from hosts administered CCl4 orally twice a week for 10 weeks was the most effective to achieve sufficient fibrosis and greatest reproducibility with acceptable animal survival.

Topics: Animals; Carbon Tetrachloride Poisoning; Dimethylnitrosamine; Disease Models, Animal; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; Thioacetamide

Liver injury initiated by non-lethal doses of CCl(4) and thioacetamide (TA) progresses to hepatic failure and death of type 2 diabetic (DB) rats due to failed advance of liver cells from G(0)/G(1) to S-phase and inhibited tissue repair. Objective of the present study was to investigate cellular signaling mechanisms of failed cell division in DB rats upon hepatotoxicant challenge. In CCl(4)-treated non-diabetic (non-DB) rats, increased IL-6 levels, sustained activation of extracellular regulated kinases 1/2 (ERK1/2) MAPK, and sustained phosphorylation of retinoblastoma protein (p-pRB) via cyclin D1/cyclin-dependent kinase (cdk) 4 and cyclin D1/cdk6 complexes stimulated G(0)/G(1) to S-phase transition of liver cells. In contrast to the non-DB rats, CCl(4) administration led to lower plasma IL-6, decreased ERK1/2 activation, lower cyclin D1, and cdk 4/6 expression resulting in decreased p-pRB and inhibition of liver cell division in the DB rats. Furthermore, higher TGFbeta1 expression and p21 activation may also contribute to decreased p-pRB in DB rats compared to non-DB rats. Similarly, after TA administration to DB rats, down-regulation of cyclin D1 and p-pRB leads to markedly decreased advance of liver cells from G(0)/G(1) to S-phase and tissue repair compared to the non-DB rats. Hepatic ATP levels did not differ between the DB and non-DB rats obviating its role in failed tissue repair in the DB rats. In conclusion, decreased p-pRB may contribute to blocked advance of cells from G(0)/G(1) to S-phase and failed cell division in DB rats exposed to CCl(4) or TA, leading to progression of liver injury and hepatic failure.

Topics: Adenosine Triphosphate; Animals; Carbon Tetrachloride Poisoning; Cell Cycle; Chemical and Drug Induced Liver Injury; Cyclin D1; Cyclin-Dependent Kinases; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Immunoblotting; Interleukin-6; Liver Diseases; Male; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; Retinoblastoma Protein; Thioacetamide; Transforming Growth Factor beta1

To investigate the effects of leptin administration on liver fibrosis induced by thioacetamide (TAA).. Twenty-four male C57Bl/6 mice were randomly allocated into four groups, which were intra-peritoneally given saline (2 mL/kg), leptin (1 mg/kg), TAA (200 mg/kg), TAA (200 mg/kg) plus leptin (1 mg/kg) respectively, thrice a week. All mice were killed after 4 wk. The changes in biochemical markers, such as the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and superoxide dismutase (SOD), malondialdehyde (MDA) in liver were determined. For histological analysis, liver tissues were fixed with 10% buffered formalin, embedded with paraffin. Hematoxylin-eosin (HE) staining and picric acid-Sirius red dyeing were performed. The level of alpha1(I) procollagen mRNA in liver tissues was analyzed by RT-PCR.. Apparent liver fibrosis was found in TAA group and TAA plus leptin group. Compared to saline group, the levels of ALT and AST in serum and MDA in liver increased in TAA group (205.67+/-27.69 U/L vs 50.67+/-10.46 U/L, 177.50+/-23.65 U/L vs 76.33+/-12.27 U/L, 2.60+/-0.18 nmol/mg pro vs 1.91+/-0.14 nmol/mg pro, P<0.01) and in TAA plus leptin group (256.17+/-22.50 U/L vs 50.67+/-10.46 U/L, 234.17+/-27.37 U/L vs 76.33+/-12.27 U/L, 2.97+/-0.19 nmol/mg pro vs 1.91+/-0.14 nmol/mg pro, P<0.01). The level of SOD in livers decreased (51.80+/-8.36 U/mg pro vs 81.52+/-11.40 U/mg pro, 35.78+/-6.11 U/mg pro vs 81.52+/- 11.40 U/mg pro, P<0.01) and the level of alpha1(I) procollagen mRNA in liver tissues also increased (0.28+/-0.04 vs 0.11+/- 0.02, 0.54+/-0.07 vs 0.11+/-0.02, P<0.01). But no significant changes were found in leptin group and saline group. Compared to TAA group, ALT, AST, MDA, and alpha1(I) procollagen mRNA and grade of liver fibrosis in TAA plus leptin group increased (256.17+/-22.50 U/L vs 205.67+/- 27.69 U/L, P<0.05; 234.17+/-27.37 U/L vs 177.50+/-23.65 U/L, P<0.05; 2.97+/-0.19 nmol/mg pro vs 2.60+/-0.18 nmol/mg pro, P<0.05; 0.54+/-0.07 vs 0.28+/-0.04, P<0.01; 3.17 vs 2.00, P<0.05), and the level of SOD in liver decreased (35.78+/-6.11 U/mg pro vs 51.80+/-8.36 U/mg pro, P<0.05). There were similar changes in the degree of type I collagen deposition confirmed by picric acid-Sirius red dyeing.. Leptin can exacerbate the degree of TAA-induced liver fibrosis in mice. Leptin may be an important factor in the development of liver fibrosis.

Topics: Animals; Carbon Tetrachloride Poisoning; Collagen; Disease Models, Animal; DNA Primers; Drug Antagonism; Leptin; Liver Cirrhosis, Experimental; Liver Function Tests; Malondialdehyde; Mice; Procollagen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Superoxide Dismutase; Thioacetamide

To study the hepatoprotective effect of the aerial parts and the roots of G. scabra on cute liver injury models.. Acute liver injury models were induced by CCl4, TAA and D-GlanN in mice, and the levels of serum enzyme ALT, AST and AKP on acute liver injury mice with extracts of theaerial parts and the roots of G. scabra were determined.. Different dosages of theaerial part extract could significantly reduce the levels of serum enzyme ALT, AST and AKP (P < 0.05) on CCl4 and TAA model mice, but the serum enzymes reduction of D-GlanN model mice was not remarkably.. The methanolic extracts of the aerial parts and the roots of G. scabra both have certain hepatoprotective effects on acute liver injury models, and so the aerial parts of G. scabra can be used as the succedaneumm of G. scabra roots.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Female; Galactosamine; Gentiana; Male; Mice; Plant Components, Aerial; Plant Roots; Plants, Medicinal; Random Allocation; Thioacetamide

The hepatic lesion produced as a result of oxidative stress is of wide occurrence. In the present study, the effect of tungsten on liver necrosis and fulminant hepatic failure (FHF) has been studied in rats treated with various compounds known to produce oxidative stress. Supplementation of animals with sodium tungstate for 7 weeks before the induction of liver injury by chemicals including thioacetamide (TAA), carbon tetrachloride (CCl(4)), or chloroform (CHCl(3)) could protect progression of hepatic injury. Various biochemical changes associated with liver damage and oxidative stress were measured. Hepatic malondialdehyde content, endogenous tripeptide, and reduced glutathione were measured as oxidative stress markers. The activity of xanthine oxidase, which generates reactive oxygen species (ROS) as a by-product, was also determined and found to be perturbed. Tungsten supplementation to rats caused a significant decrease in lipid peroxidation and lowered the levels of the biochemical markers of hepatic lesions produced by TAA, CCl(4) (CCl(4)), or CHCl(3). Tungsten could also cause an increase in the survival rate in rats receiving lethal doses of TAA, CCl(4), or CHCl(3). The protective effect of tungsten, however, is suggested to be limited to the conditions where the hepatic lesion is reported to be due to the generation of ROS. The progression of liver injury produced by the compounds causing oxidative stress without initiating the generation of free radicals such as bromobenzene (BB), or acetaminophen (AAP), could not be inhibited by tungsten. The possible mechanism explaining the role of oxyanionic form of tungsten in free radical-induced hepatic lesions is discussed.

Topics: Acetaminophen; Alkaline Phosphatase; Allopurinol; Animals; Bromobenzenes; Carbon Tetrachloride Poisoning; Chloroform; Dimethyl Sulfoxide; Female; Lethal Dose 50; Liver; Liver Failure; Necrosis; Oxidative Stress; Rats; Rats, Wistar; Thioacetamide; Transaminases; Tungsten Compounds

Hepatoprotective activity of 3-bromo-6-(4-chlorophenyl)-4-methylthio-2H-pyran-2-one, an isostere of dimethyl ricinine, was evaluated in adult male albino rats intoxicated with carbon tetrachloride, paracetamol or thioacetamide. The test compound showed significant hepatoprotection at 6.0 mg kg(-1) body mass daily dose, given to the rats for seven consecutive days. The carbon tetrachloride, paracetamol and thioacetamide were given, respectively, on days 3, 5, and 7, on day 6 and on day 6 post treatment with the test compound. The protective effect was evident in a battery of serum and liver biochemical parameters related to hepatotoxicity.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Carbon Tetrachloride Poisoning; Carcinogens; Chemical and Drug Induced Liver Injury; Cholesterol; DNA; Hydrocarbons, Halogenated; Liver; Liver Function Tests; Liver Glycogen; Male; Protein Biosynthesis; Pyrones; Rats; Rats, Sprague-Dawley; RNA; Thioacetamide

Lines of evidence suggested a possible link between leptin and hepatic fibrosis; however, whether leptin modulates the fibrogenesis in the liver remains unclear. The purpose of this study, therefore, was to evaluate the effect of leptin on inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. Male C57Bl/6 mice were given carbon tetrachloride (CCl(4)) (0.1 microL/g body weight [BW], intraperitoneally [IP]) and/or recombinant murine leptin (1 microg/g BW, IP) simultaneously, and sacrificed up to 72 hours later. Further, some mice were given thioacetamide (TAA; 200 microg/g BW, IP) and leptin 3 times per week for 4 weeks to evaluate the effect of leptin on chronic fibrogenic responses. A simultaneous injection of leptin enhanced acute CCl(4)-induced necroinflammatory and subsequent fibrotic changes in the hepatic lobules. The steady-state messenger RNA (mRNA) levels of alpha1(I) procollagen and heat shock protein 47 (HSP47) in the liver were potentiated when leptin was injected together with CCl(4). Expression of alpha smooth muscle actin (alpha-SMA) in the liver after CCl(4) treatment was also augmented markedly in combination with leptin. Further, leptin increased transforming growth factor beta1 (TGF-beta1) mRNA in the liver 24 hours after acute CCl(4) about 4-fold higher than CCl(4) alone. Moreover, leptin enhanced hepatic fibrosis and induction of alpha1(I) procollagen mRNA caused by chronic TAA administration. Collectively, these findings indicated that leptin augments both inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. It is postulated that the increase in systemic leptin levels enhances up-regulation of TGF-beta1, leading to activation of stellate cells, thereby augmenting the fibrogenic response in the liver.

Topics: Actins; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Endotoxins; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Leptin; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth; Portal System; Procollagen; RNA, Messenger; Thioacetamide; Transaminases; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The protective effects of 1,3-dithia-2-thioxo-cyclopent-4-ene (DT827A),4-phenyl-1,3-dithia-2-thioxo-cyclopent- 4-ene (DT827B) and 4-(4-fluorophenyl)-1,3-dithia-2-thioxo-cyclopent-4-ene (DT827C) on liver injury induced by D-galactosamine plus carbon tetrachloride (D-GalN + CCl4) and that of DT827B on liver injury induced by thioacetamide were studied using male rats. Out of the three DT827 series of compounds, DT827B was more effective on liver injury induced by the combination exposure to D-GalN + CCl4 for 4 weeks, and accordingly the following two experiments were carried out using DT827B only. Twelve-week administration of DT827B at dose levels of 5, 10 and 20 mg/kg/day revealed a therapeutic effect against liver injury induced by D-GalN + CCl4 dose-dependently, and another twelve-week administration of DT827B at the same three dose levels also revealed a therapeutic effect against liver injury induced by thioacetamide dose-dependently. A hepatoprotective potential of DT827B was suggested under the conditions of these studies.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Galactosamine; Heterocyclic Compounds, 1-Ring; Liver Diseases; Male; Rats; Rats, Wistar; Thioacetamide; Thiones

Oral administration of two doses of corynoline, acetylcorynoline or protopine at 50 and 100 mg.kg-1 in an interval of 8 to 24 h before i.p. injection of CCl4, acetaminophen or thioacetamide significantly impeded the elevation of serum transaminase (SGPT) and liver damage in mice. The three compounds were found to inhibit CCl4-induced microsomal lipid peroxidation and CCl4 conversing to carbon monoxide in liver microsomes in vitro. Of these compounds, acetylcorynoline was shown to be more potent than corynoline and protopine. In addition, all the three compounds exhibited biphasic effects on the hepatic cytochrome P450, i.e. inhibition followed by induction, in mice.

Topics: Acetaminophen; Alanine Transaminase; Alkaloids; Animals; Benzophenanthridines; Berberine Alkaloids; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Liver; Male; Mice; Microsomes, Liver; Thioacetamide

We have shown that urinary taurine level may be used as a biomarker of pathological and biochemical lesions. Detection of changes in the urinary concentration of this low molecular weight metabolite indicates biochemical lesions which may also be associated with pathological damage. Hepatotoxic compounds such as CCl4, galactosamine and thioacetamide that cause hepatic necrosis and compounds such as hydrazine and ethionine that cause fatty liver all result in elevated urinary taurine levels in rats. However compounds which do not cause liver damage, such as cycloheximide, also raise urinary taurine levels. All of these substances are known to or are believed to inhibit protein synthesis. Conversely, compounds which increase protein synthesis, such as phenobarbital and clenbuterol, significantly decrease urinary taurine levels. Compounds which interfere with hepatic GSH synthesis will also change urinary taurine levels. Thus, depletion of GSH with diethyl maleate or phorone decreases urinary taurine whereas inhibition of GSH synthesis with compounds such as buthionine sulphoximine increases urinary taurine levels. In isolated hepatocytes in vitro, leakage of taurine occurs in response to cytotoxic compounds such as hydrazine and allyl alcohol. However, total taurine levels were increased by the hepatotoxicant CCl4. Taurine synthesis is decreased by depletion of GSH with allyl alcohol in isolated hepatocytes. Therefore taurine levels are an important potential biomarker for biochemical lesions induced by chemicals both in vivo and in vitro, in particular changes in protein and GSH synthesis.

Topics: Animals; Biomarkers; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Cells, Cultured; Clenbuterol; Galactosamine; Glutathione; Ketones; Liver; Liver Diseases; Male; Maleates; Necrosis; Phenobarbital; Rats; Rats, Sprague-Dawley; Taurine; Thioacetamide

Blumeatin (Blu, 5,3',5'-trihydroxy-7-methoxy-dihydro-flavone) was first isolated from Blumea balsamifera DC by Department of Chemistry, Sunyatsen University of China. Blu ip inhibited the increase of serum alanine aminotransferase (AAT) and liver triglyceride and increased serum triglyceride, beta-lipoprotein, and liver glycogen content in CCl4-intoxicated rats. Histological lesions of liver were less severe than those of hepatic injury control. Blu ip 0.65 and 3.25 mg.kg-1 inhibited the increase of serum AAT and hepatic TG in thioacetamide (TAA)-intoxicated mice. Blu ip shortened the pentobarbital sleeping time in CCl4-intoxicated mice. It suggested that Blu could protect liver against injury induced by CCl4 and TAA.

Topics: Alanine Transaminase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Female; Flavonoids; Liver; Male; Mice; Rats; Rats, Sprague-Dawley; Thioacetamide; Triglycerides

By means of statistical pattern recognition procedures, a quantitative description of the ultrasound B-scan images of experimental diffuse liver disease has been carried out. Fatty livers, fatty fibrosis/cirrhosis, and cirrhosis without fatty infiltration of the liver were studied in female Wistar rats. Separation accuracies of more than 80% between the tissue classes "normal" vs "fatty infiltration," or "normal" vs "fatty cirrhosis," using only two statistical image parameters were found. A subclassification of the diffuse parenchymal liver disease was not possible. It is shown by multiple linear regression analysis that the image parameter "mean grey level" correlates better with total lipid content than with the amount of connective tissue. Furthermore it is demonstrated that connective tissue leads only to a weak increase in "mean grey level," whereas the addition of connective tissue to a given tissue lipid can lead to a reduction in image brightness.

Topics: Animals; Carbon Tetrachloride Poisoning; Connective Tissue; Fatty Liver; Female; Image Processing, Computer-Assisted; Liver Cirrhosis, Experimental; Rats; Rats, Inbred Strains; Thioacetamide; Ultrasonography

The urinary excretion of taurine by rats after dosing with various hepatotoxins has been investigated by 1H NMR spectroscopy. After single hepatotoxic doses of hydrazine, carbon tetrachloride, 1-naphthylisothiocyanate, or thioacetamide there was biochemical and histopathological evidence of hepatic damage. Proton NMR spectroscopy of the urine collected for 24 h after dosing from these animals revealed a marked elevation in taurine (control 11.9 mumole/h/kg) after dosing with thioacetamide (42.2 mumole/h/kg), carbon tetrachloride (52.5 mumole/h/kg), 1-naphthyl-isothiocyanate (80.4 mumole/h/kg) and hydrazine (52.9 mumole/h/kg). After allyl alcohol administration there was no increase in taurine excretion (7.5 mumol/h/kg). The excretion of taurine after hydrazine administration was dose related. High resolution proton NMR spectroscopic analysis of urine also revealed resonances from several metabolites of hydrazine, an N-acetylcysteine conjugate of allyl alcohol, and acetamide as a metabolite of thioacetamide after dosing with the respective compounds. Changes in endogenous substances that may be related to the pathological events were also detected, such as a decrease in the excretion of 2-oxoglutarate and citrate after both hydrazine and carbon tetrachloride administration. The results confirm that proton NMR spectroscopic analysis of urine is a powerful analytical tool for the evaluation and study of toxic substances. Furthermore, measurement of urinary taurine may provide a non-invasive indicator of acute hepatic damage with certain classes of hepatotoxins.

Topics: 1-Naphthylisothiocyanate; Alanine Transaminase; Animals; Aspartate Aminotransferases; Bilirubin; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Hydrazines; Magnetic Resonance Spectroscopy; Male; Protons; Rats; Taurine; Thioacetamide

Kopsinine F is an indole alkaloid. The present studies show that prior oral administration of kopsinine F 150 mg/kg significantly protected mice from liver injuries induced by intraperitoneal injection of CCl4, thioacetamide and acetaminophen. The alkaloid also inhibited CCl4 induced lipid peroxidation (MDA formation) of liver microsomes and 14CCl4 covalent binding to lipids of liver microsomes in vitro. In addition, kopsinine F significanty induced hepatic microsomal cytochrome P-450 in mice. The results indicate that kopsinine F has hpatoeprotective activity in mice.

Topics: Acetaminophen; Alkaloids; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Lipid Peroxidation; Male; Mice; Microsomes, Liver; Thioacetamide

Sulphoxidation of cimetidine was investigated in male and female rats after pretreatment with the hepatotoxins allyl alcohol, dl-ethionine, thioacetamide and carbon tetrachloride. There was a marked sex difference in cimetidine sulphoxidation in response to the hepatotoxin pretreatment. All the hepatotoxins enhanced cimetidine sulphoxidation in the male rat (P less than 0.01). Carbon tetrachloride and thioacetamide inhibited cimetidine sulphoxidation in the female rat (P less than 0.01) but dl-ethionine and allyl alcohol had no effect on this metabolic pathway.

Topics: 1-Propanol; Animals; Bromobenzenes; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cimetidine; Propanols; Rats; Rats, Inbred Strains; Sulfoxides; Thioacetamide

Altered transport of nuclear RNA sequences is an early response to carcinogens. Nuclear envelopes (NE) were isolated and assayed for nucleoside triphosphatase activity (NTPase), on the premise that this enzymatic activity participates in RNA transport. A common feature of the action of five different carcinogens (thioacetamide, 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, dimethylnitrosamine, and aflatoxin B1), at low doses without significant toxicity, was to increase NE NTPase activity and to increase RNA transport, as assessed by the appearance of rapidly labeled RNA in the cytoplasm and by in vitro assay. The increases in NTPase were specific for the NE fraction, and early toxic effects of higher doses initially masked the increases. The induced increases in NE NTPase were long-lived. In contrast, increases in NE NTPase were observed only during the regenerative phase of CCl4 intoxication; the CCl4-induced increase was short-lived and returned promptly to control levels. These changes in NTPase activity were not associated with parallel changes in phosphorylation/dephosphorylation of NE proteins. Increases in NE NTPase and alterations in RNA transport, without attendant nuclear replication, may relate to altered nuclear RNA restriction. This change in a regulatory phenomenon may make these cells more susceptible to further modification, potentially playing a role in the initiation phase of carcinogenesis.

Topics: 2-Acetylaminofluorene; Aflatoxin B1; Aflatoxins; Animals; Biological Transport; Carbon Tetrachloride Poisoning; Carcinogens; Dimethylnitrosamine; Kinetics; Liver; Male; Methyldimethylaminoazobenzene; Nuclear Envelope; Nucleoside-Triphosphatase; Phosphoric Monoester Hydrolases; Phosphorylation; Rats; Rats, Inbred Strains; RNA; Thioacetamide

Changes in activities of a new proteinase cathepsin T as well as some other lysosomal acid proteinases and hydrolases were examined in liver homogenate from rats treated with a single hepatotoxic dose of carbon tetrachloride. The most striking changes were several-fold increases of liver cathepsin T and D activities over their levels in untreated rats 3 days after administration of the agent to rats. Increase of cathepsin T was greater than that of cathepsin D at all doses of the hepatotoxin examined. The activities of N alpha-benzoyl-DL-arginine 2-naphthylamide hydrolase, acid phosphatase, beta-galactosidase and beta-glucuronidase in poisoned rat liver were unchanged or only slightly increased. Cathepsin T and D activities were less enhanced in mitochondrial lysosomal fractions than in the homogenate, and were greatly elevated in the supernatant fractions of liver from the treated rats. As judged from the molecular weights, the elevated activities of cathepsins T and D in the treated rat liver could be attributable to the two cathepsins themselves and not to other proteinases. Administration to rats of other hepatotoxic agents, thioacetamide and dimethylnitrosamine, also induced the elevation of the two cathepsin activities in liver, but on partial hepatectomy the activities of liver cathepsins T and D did not show such marked increases. Nonparenchymal liver cell fractions were responsible for almost all the increased activities of liver cathepsins T and D. It is possible that cathepsins T and D play a role in the heterolytic breakdown of hepatocyte molecules following CCl4 poisoning.

Topics: Animals; Carbon Tetrachloride Poisoning; Cathepsin D; Cathepsins; Dimethylnitrosamine; Hepatectomy; Liver; Male; Rats; Rats, Inbred Strains; Thioacetamide; Tissue Distribution

To study the relationship between lipid peroxidation and cellular damage we studied three compounds known to evoke lipid peroxidation (cumene hydroperoxide, CHP), hepatocellular injury (thioacetamide, TAA) or both (carbon tetrachloride, CCl4). Phenobarbital-induced male rats were treated with one of the three agents and lipid peroxidation was monitored via the measurement of exhaled ethane. Treatment with both, CCl4 and CHP resulted in an increased ethane expiration, whereas TAA did not. When liver-specific serum enzyme activities (GPT, SDH) were investigated 24 h later, however, hepatotoxicity was evident only in rats treated with either CCl4 or TAA. The ATP-dependent Ca2+-sequestration activity of microsomal membranes, suggested to be a final common pathway leading to cellular death, was studied in microsomes isolated from rats treated with either agent. 2 h after treatment with CCl4 or TAA a clear inhibition was seen which persisted after 24 h in the case of CCl4 only. CHP did not affect the Ca2- -pump activity. Thus, a clear correlation between cellular damage and lipid peroxidation cannot be expected in every case. An impairment of the microsomal calcium-pump, however, seems to be a crucial event which leads to hepatocellular injury.

Topics: Animals; Benzene Derivatives; Calcium; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Lipid Peroxides; Male; Microsomes, Liver; Rats; Rats, Inbred Strains; Thioacetamide; Time Factors

Topics: Acetamides; Animals; Carbon Tetrachloride Poisoning; Glutathione; Glutathione Transferase; Hepatectomy; Liver; Male; Rats; Rats, Inbred Strains; Thioacetamide; Time Factors

The excretion of ascorbic acid and hippuric acid in the urine as liver function tests has no marked advantages when compared with other tests (activities of serum enzymes glutamate dehydrogenase and L-alanine: 2-oxoglutarate aminotransferase, hexobarbital sleeping time).

Topics: Aminopyrine; Animals; Ascorbic Acid; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Female; Hexobarbital; Hippurates; Male; Rats; Sleep; Thioacetamide; Time Factors

In rats, 3 days treatment with paracetamol (1 oral dose of 1 g/kg daily) produced a complete protection against the hepatotoxic actions of a further dose of paracetamol as documented by determination of serum enzyme activities (glutamic-oxaloacetic transaminase, (GOT), glutamic-pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), bromsulphthalein retention and histological investigations. Subacute paracetamol treatment decreased liver glutathione levels by 46%, liver microsomal cytochrome P-450 content by 23%, hepatic hydroxylation of aniline by 29% and hepatic demethylation of aminopyrine by 46%. It afforded also some protection against the hepatotoxic actions of carbon tetrachloride, bromobenzene and thioacetamide, but did not influence the antiphlogistic activity of paracetamol (carrageenan paw edema test). Plasma and liver concentrations of free paracetamol after oral administration of 1 g/kg paracetamol were somewhat higher in the subacutely paracetamol-pretreated rats than in the non-pretreated control animals whereas no differences in the concentrations of conjugated paracetamol were found between the 2 groups. Pretreatment with paracetamol did not influence the urinary excretion of free paracetamol but caused some shift in the urinary excretion of paracetamol conjugates: pretreated rats excreted 23% less of the paracetamol glucuronide and sulfate and 33% more of the paracetamol mercapturate than the control animals. A depression of the microsomal mixed-function oxidase activity is presumed to be the main cause of the paracetamol-induced protection against paracetamol hepatotoxicity.

Topics: Acetaminophen; Animals; Bromobenzenes; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Tolerance; Liver; Liver Function Tests; Male; Mixed Function Oxygenases; Rats; Thioacetamide

The authors investigated the effects of the administration of thioacetamide, carbon tetrachloride and aminophenazone on the excretion of ascorbic acid and hippuric acid in adult male and female Wistar rats. After a single application of thioacetamide and aminophenazone, the ascorbic acid content in the urine showed a dose-dependent increase, whereas that in the liver had decreased. This increase in the urinary ascorbic acid might be due to a release of stored ascorbic acid from the liver cells. When thioacetamide was given for a prolonged period, the ascorbic acid content in the urine increased at the beginning; later one, at the end of three weeks, it was slightly inferior to the control value. Both single and repeated applications of thioacetamide led to a decrease in the excretion of hippuric acid in the urine, which is attributed to an impairment of the mitochondrial hippuric acid synthesis. Long-term treatment with aminophenazone resulted in an increase of ascorbic acid in the urine, which is indicative of an induction effect, whereas the ascorbic acid content in the liver remained unchanged. There was no effect on the excretion of hippuric acid. In regard to their use in the toxicological evaluation of drugs, these two metabolic effects offer no decisive advantage over current liver function tests.

Topics: Aminopyrine; Animals; Ascorbic Acid; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Enzymes; Female; Hexobarbital; Hippurates; Liver; Liver Function Tests; Male; Rats; Sleep; Thioacetamide; Time Factors

Topics: Allyl Compounds; Aniline Hydroxylase; Animals; Bromobenzenes; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Dimethylnitrosamine; Ditiocarb; Male; Mice; Sulfhydryl Compounds; Sulfur; Thioacetamide; Thiocarbamates

The hepatotoxic effects of carbon tetrachloride (0.01 ml/kg i.p.), thioacetamide (50 mg/kg intraperitoneally), paracetamol (0.5 g/kg intraperitoneally), and allyl alcohol (0.05 ml/kg intraperitoneally) as estimated by determination of serum enzyme activities (GOT, GPT, SDH) were enhanced in mice treated with one oral dose of 4.8 g/kg ethanol 16 hrs. previously. Pretreatment of mice with ethanol did not increase the hepatotoxic actions of bromobenzene (0.25 ml/kg intraperitoneally), phalloidin (1.5 mg/kg intraperitoneally), alpha-amanitin (0.75 mg/kg intraperitoneally), and praseodymium (12 mg/kg intravenously) though there was a trend to higher enzyme activities in the case of bromobenzene. In guinea-pigs ethanol also aggravated CCl4-induced liver damage, but only strengthened the hepatotoxic activity of D-galactosamine (150 mg/kg intraperitoneally). Treatment with 4.8 g/kg ethanol did not influence liver glutathione levels in mice but increased aniline hydroxylation in the 9000 x g liver homogenate supernatant of mice and guinea-pigs. A dose of 2.4 g/kg ethanol, on the other hand, neither increased aniline hydroxylase activity nor enhanced carbon tetrachloride-induced hepatotoxicity in mice. It is assumed that the enhanced sensitivity to hepatotoxic agents after treatment with ethanol may be due to an enhanced microsomal activation of these substances.

Topics: Acetaminophen; Administration, Oral; Alanine Transaminase; Alcoholic Intoxication; Amanitins; Aniline Hydroxylase; Animals; Aspartate Aminotransferases; Bromobenzenes; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Ethanol; Galactosamine; Glutathione; Humans; L-Iditol 2-Dehydrogenase; Liver; Male; Mice; Microsomes, Liver; Organ Size; Phalloidine; Praseodymium; Thioacetamide

The liver protective effect of Aicaphosphate in CC1(4)-induced acute, as well as CC1(4)-and thioacetamide-induced subacute and chronic liver damages is demonstrated. The effect of the protective drugs was studied in the forms of pre-, simultaneous and delayed treatment in acute and chronic liver damages induced by various toxic agents. The degree of liver damage was determined by morphological and biochemical methods, complementary to each other. For the completion of histological studies and morphometry used for the determination of the degree of fibrosis biochemical investigations are performed. In acute liver damage the determination of DNA, protein and lipid contents of the liver tissue and the radioactive aminoacid incorporation rate should be carried out with a simultaneous analysis of the serum enzymes. In chronic liver damage, the measurement of the hydroxyproline and DNA contents of the liver give useful data for the determination of the severity of the lesion and the effect of the protective drugs, respectively.

Topics: Acetamides; Aminoimidazole Carboxamide; Animals; Carbon Tetrachloride Poisoning; Disease Models, Animal; Female; Imidazoles; Liver; Liver Cirrhosis, Experimental; Male; Rats; Thioacetamide

Possible differences in the mechanisms of increased alpha1-fetoprotein (AFP) production following carbon tetrachloride (CCl4) intoxication and partial hepatectomy were studied with 5-week-old rats at the time of sacrifice. The maximum level of serum AFP reached in 4 days after a single dose of CCl4 was much higher than that after partial hepatectomy, although the incorporation of [3H]thymidine into liver DNA increased nearly to the same extent by either of these treatments. In the remnant after partial hepatectomy, the DNA synthesis that was further accelerated by treatment with a lower dose of thioacetamide was not associated with any further increases of serum AFP levels. However, CCl4 given to partially hepatectomized rats had an additive effect on increased AFP levels. The increases of serum AFP concentrations in CCl4-injured rats had an additive effect on increased AFP levels. The increases of serum AFP concentrations in CCl4-injured rats were depressed by Mitomycin C given in vivo, whereas the increases in partially hepatectomized rats were not. Treatment with 8-azaguanine inhibited both increase of serum AFP levels, although the inhibition was much less or was insignificant in partially hepatectomized rats. These results suggest that existence of different underlying mechanisms of the increased AFP production for the two experimental conditions.

Topics: alpha-Fetoproteins; Animals; Azaguanine; Carbon Tetrachloride Poisoning; DNA; Fetal Proteins; Glucosephosphate Dehydrogenase; Hepatectomy; Liver; Liver Regeneration; Male; Mitomycins; Organ Size; Rats; Thioacetamide; Transcription, Genetic

The temporal sequence of alpha-fetoprotein appearance in serum was determined in both necrogenic and nonnecrogenic liver injury. Ethionine, thioacetamide, and CCl4 were used to intoxicate male and female rats for evaluating serum enzyme levels, mitotic indices, and morphological reflections of impairment. Thioacetamide- and CCl4-induced cell death preceded the mitotic wave in residual hepatocytes, and, in the case of both agents, this intoxicant-mediated necrosis preceded the emergence of alpha-fetoprotein. Yet, although there was no evidence of either cell destruction or significant mitotic activity in ethionine-poisoned animals, serum alpha-fetoprotein levels progressively increased. Thus the temporal sequence of alpha-fetoprotein synthesis and/or release and cellular reorganization for regeneration suggests that reappearance of the protein macro-molecule is an expression of the altered phenotype observed during the "step-down" phase of liver regeneration.

Topics: Alanine Transaminase; alpha-Fetoproteins; Animals; Aspartate Aminotransferases; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Ethionine; Female; Liver Diseases; Liver Regeneration; Male; Mitosis; Necrosis; Rats; Thioacetamide; Time Factors

Topics: 1-Propanol; Acetaldehyde; Acetamides; Alanine Transaminase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Dimethylnitrosamine; Drug Synergism; Ethanol; Lipid Metabolism; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Nitrosamines; Rats; Thioacetamide

Topics: Alanine Transaminase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Male; Medicine, East Asian Traditional; Mice; Plant Extracts; Plants, Medicinal; Quinestrol; Rabbits; Rats; Thioacetamide

Topics: Acetamides; Alanine Transaminase; Alcohols; Allyl Compounds; Animals; Benzene Derivatives; Body Temperature; Bromine; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Dibenzylchlorethamine; Dose-Response Relationship, Drug; Female; Hydrocarbons, Brominated; Lethal Dose 50; Liver; Male; Mice; Nitrosamines; Phenoxybenzamine; Quinolines; Rats; Thioacetamide; Time Factors; Tolazoline; Triglycerides

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cholestasis; Cholinesterases; Clinical Enzyme Tests; Diagnosis, Differential; Ethionine; Fatty Liver; Fructose-Bisphosphate Aldolase; Fructosephosphates; Necrosis; Phenobarbital; Proadifen; Rats; 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; 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 Tetrachloride Poisoning; Duodenum; Liver; Nucleoproteins; Pancreas; Phosphorus; Proteins; Rats; Research; Serum Albumin; Sulfur; Thioacetamide; Toxicology; Valine