diethyl-maleate and Chemical-and-Drug-Induced-Liver-Injury

The protective role of Tropaelum majus (T.majus) methyl alcohol extract and vitamin E in the case of toxic effect induced by diethyl maleate was evaluated. Forty-two male albino rats were divided into seven groups of six rats each for 15 days. Group 1: normal control group. Group 2: taken daily oral dose of paraffin oil (0.25ml/100g b.wt rat). Group 3: received daily oral dose of vitamin E (100mg/kg b.wt rat). Group 4: taken daily oral dose of 10% of the LD50 of T.majus methyl alcohol extract. Groups 5–7: injected intra-peritoneally with diethyl maleate (5 μl/100g b.wt rat) but groups 6 and 7 received a daily oral dose of either vitamin E or 10% of the LD50 of T.majus methyl alcohol extract 1h prior to diethyl maleate injection. The present results revealed that diethyl maleate induced serum aspartate and alanine aminotransferases enzymes activities decreased in serum, but their activities in the hepatic tissue showed an increase. Glutathione and glucose-6-phosphate dehydrogenase levels showed a decrease, but thiobarbituric acid reactive substances level showed an increase in both serum and liver tissue. Serum and liver proteins decreased in serum and liver tissue. A significant decrease in blood parameters (hemoglobin, hematocrit, as well as red and white blood cells) and serum glucose occurred. Histopathological results showed that diethyl maleate induced a hoop of edema in the hepatic periportal area; while T.majus methyl alcohol extract or vitamin E prior to diethyl maleate injection shift blood and liver toxicity induced by diethyl maleate towards normal values and preserved hepatic lobular architecture. In conclusion, pre-treatment with either T.majus methyl alcohol extract or vitamin E provide protection against blood and liver toxicity induced by diethyl maleate in rats, these results were confirmed by histological examinations.

Topics: Alanine Transaminase; Animals; Aspartic Acid; Chemical and Drug Induced Liver Injury; Lethal Dose 50; Liver; Male; Maleates; Plant Extracts; Protective Agents; Rats; Tropaeolum

Prior induction of peroxisome proliferation protects mice against the in vivo hepatotoxicity of acetaminophen and various other bioactivation-dependent toxicants. The mechanisms underlying such chemoresistance are poorly understood, although they have been suggested to involve alterations in glutathione homeostasis. To clarify the role of glutathione in this phenomenon, we isolated hepatocytes from mice in which hepatic peroxisome proliferation had been induced with clofibrate. The cells were incubated with a range of acetaminophen concentrations and the extent of cell killing after up to 8 h was assessed by measuring lactate dehydrogenase leakage from the cells. Hepatocytes from clofibrate-pretreated mice were much less susceptible to acetaminophen than cells from vehicle-treated controls. However, the extent of glutathione depletion during exposure to acetaminophen was similar in both cell types, as were rates of excretion of the product of glutathione-mediated detoxication of acetaminophen's quinoneimine metabolite, 3-glutathionyl-acetaminophen. The glutathione-replenishing ability of clofibrate-pretreated cells after a brief exposure to diethyl maleate also resembled that of control cells. More importantly, prior depletion of glutathione by diethyl maleate did not abolish the resistance of clofibrate-pretreated cells to acetaminophen. Taken together, these findings indicate that although glutathione-dependent pathways may contribute to hepatoprotection during peroxisome proliferation, the resistance phenomenon is not due exclusively to this mechanism.

Topics: Acetaminophen; Animals; Antidotes; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Clofibrate; Dose-Response Relationship, Drug; Drug Antagonism; Glutathione; Homeostasis; L-Iditol 2-Dehydrogenase; L-Lactate Dehydrogenase; Liver; Male; Maleates; Mice; Peroxisome Proliferators

Mediators of inflammation modulate the extent of hepatocellular necrosis following the administration of hepatotoxins. Since corticosteroids interfere with the generation of some of these mediators they might thus protect against the hepatotoxicity of drugs such as acetaminophen. To test this hypothesis mice were pretreated with two doses of prednisolone (10 and 20 mg/kg i.p., 17 and 2 h, respectively) prior to a hepatotoxic dose of 375 mg/kg acetaminophen and the metabolism and toxicity of acetaminophen were assessed. Twenty-four hours after acetaminophen the activity of ALT in plasma (737 vs. 6775 U/l) and the extent of hepatocellular necrosis (4 vs. 45% necrotic hepatocytes) were significantly lower in prednisolone-pretreated mice. Prednisolone pretreatment resulted in decreased covalent binding of the toxic metabolite in vivo and an increased urinary excretion of glutathione-derived conjugates of acetaminophen, indicating an enhanced detoxification of the reactive metabolite by glutathione. Nevertheless, hepatic glutathione was less depleted by acetaminophen in the prednisolone group, indicating an increased capacity to resynthesize glutathione. This was confirmed in experiments with diethyl maleate which depletes hepatic glutathione without causing cell injury. Following the administration of diethyl maleate to fed and fasted mice, hepatic glutathione was depleted to the same extent after 45 min, but was significantly higher after 2.5 h in prednisolone-pretreated mice. The present results indicate that prednisolone increases the capacity to replete depleted hepatic glutathione stores in mice.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Glutathione; Liver; Male; Maleates; Mice; Mice, Inbred Strains; Prednisolone; Protein Binding

Metallothionein (MT) is a sulfhydryl-rich protein whose levels are increased by administration of a variety of agents including metals, cytokines, and oxidative stress agents. Recent studies have suggested that MT is involved in protecting against various forms of oxidative stress, but little is known about the induction of MT by oxidative stress agents. Diethyl maleate (DEM) causes oxidative stress by depleting glutathione levels and is quite effective at increasing hepatic concentrations of MT. The purpose of the current study was to learn more about the relationship between induction of MT and oxidative stress by characterizing this increase in hepatic MT levels produced by DEM. Administration of DEM (3 to 9 mmol/kg, sc) increased hepatic MT concentration in mice as much as 37-fold to 213 micrograms MT/g liver, which is similar to the hepatic MT level seen after administration of other effective MT inducers, such as Cd. The maximal increase of hepatic MT took place 12 to 24 hr after administration of 5 mmol DEM/kg. This rise in MT was preceded by a 60% depletion of hepatic glutathione 3 hr after DEM and increases in both MT-I and MT-II mRNA, which reached a peak 6 to 9 hr after DEM. Administration of DEM (3-5 mmol/kg, sc) also increased MT levels in Sprague-Dawley rats. Pretreatment with DEM protected against Cd-induced hepatotoxicity in a fashion which suggested that a functional MT was being synthesized. In summary, DEM is a highly effective inducer of MT which increases MT at the mRNA level.

Topics: Animals; Base Sequence; Blotting, Northern; Cadmium; Chemical and Drug Induced Liver Injury; Cytosol; Dose-Response Relationship, Drug; Glutathione; Immunoblotting; Liver; Liver Diseases; Male; Maleates; Metallothionein; Mice; Mice, Inbred Strains; Molecular Sequence Data; Rats; Rats, Inbred Strains; RNA, Messenger; Subcellular Fractions; Time Factors; Transcription, Genetic

Treatment of male Sprague-Dawley rats with buthionine sulfoximine (BSO), prior to administration of carbon-14(14C)-labelled 2-methylfuran (2MF) caused a marked decrease in the covalent binding of 14C-labelled 2MF metabolites to both DNA and protein, although there was no apparent change in the distribution of the labelled parent 2MF. BSO pretreatment also protected against hepatotoxicity of 2MF, as indicated by lower serum glutamic pyruvic transaminase (GPT) levels. Pretreatment with BSO offered protection only if administered 1.5 hr before 2MF dosage. Administration of 2MF, 4 and 6 hr after BSO resulted in manifestation of the hepatotoxicity of 2MF. Prior treatment with diethylmaleate (DEM), increased covalent binding of [14C]2MF to liver proteins and also elevated serum GPT levels. Thus, depletion of tissue glutathione (GSH) by two different chemicals acting by different mechanisms produced opposite effects on the covalent binding and toxicity of 2MF. Pretreatment with L-2-oxothiazolidine-4-carboxylate (OTZ), a promoter of GSH biosynthesis, increased the hepatic covalent binding of [14C]2MF and potentiated hepatotoxicity. However, administration of OTZ and BSO prior to an i.p. dose of 100 mg/kg of 2MF, decreased the hepatic covalent binding of [14C]2MF and decreased the hepatoxicity. The marked instability of the GSH conjugate of the reactive metabolite of 2MF may account for the potentiation of hepatotoxicity of 2MF by OTZ. A single s.c. dose of BSO, caused a transient increase in plasma cystine levels concurrent with the depletion of liver GSH. Administration of 2MF, 1.5 hr after BSO, significantly decreased plasma cystine levels as compared to control animals that received vehicle alone. Pretreatment with BSO also resulted in increased excretion of urinary metabolites in 2MF treated animals as compared to animals receiving 2MF alone. Thus, BSO probably protects against hepatoxicity of 2MF by indirectly causing more detoxification of the reactive metabolite of 2MF, as it does not alter the distribution of unmetabolized 2MF and does not have any apparent effect on the microsomal mixed-function oxidase which mediates the activation of 2MF. The enhanced detoxification of 2MF in BSO treated animals appears independent of the depleted GSH levels; it may result from increased availability of a better alternative nucleophile (i.e. cysteine), capable of conjugating with acetyl acrolein. Acetyl acrolein (AA) appears to be the principal reactive metabolite of 2

Topics: Alanine Transaminase; Animals; Antimetabolites; Buthionine Sulfoximine; Chemical and Drug Induced Liver Injury; Cystine; Drug Interactions; Furans; Glutathione; Male; Maleates; Methionine Sulfoximine; Pyrrolidonecarboxylic Acid; Rats; Rats, Inbred Strains; Thiazoles; Thiazolidines

Topics: 1-Propanol; Animals; Ascorbic Acid; Bromobenzenes; Chemical and Drug Induced Liver Injury; Dehydroascorbic Acid; Diet; Glutathione; Lipid Peroxidation; Liver; Male; Maleates; Mice; Propanols; Vitamin E

Loxistatin is a possible therapeutic agent of muscular dystrophy. A single oral administration of loxistatin to male rats caused focal necrosis of the liver with inflammatory cell infiltration. The severity of the lesions was dose-dependent up to 200 mg/kg and also manifest by an increase in serum alanine aminotransferase and aspartate aminotransferase activities. Hepatic glutathione (GSH) levels decreased with a maximum 20% depletion within 5 hr after the oral administration of loxistatin. Pretreatment with diethyl maleate did not potentiate the loxistatin-induced hepatic injury. On the other hand, the hepatoprotective effect of cysteamine was observed when cysteamine was administered 24 hr before loxistatin dosing, but the effect was not observed when the antidote was administered concomitantly with loxistatin. Pretreatment of rats with phenobarbital or trans-stilbene oxide provided partial protection against the hepatotoxic effect of loxistatin. Pretreatment with SKF-525A resulted in increased hepatic injury, while pretreatment with piperonyl butoxide, cimetidine, or 3-methylcholanthrene had no effect on hepatic damage by loxistatin. Five hours after [14C]loxistatin administration to rats, the covalent binding of the radioactivity to proteins was greatest in the liver, followed by the kidney, then muscle and blood to a lesser extent. [14C]Loxistatin acid, the pharmacologically active form of loxistatin, irreversibly bound to rat liver microsomal proteins; more binding occurred when the NADPH-generating system was omitted and when the microsomes were boiled first. GSH did not alter the extent of irreversible binding, whereas N-ethylmaleimide decreased the binding of [14C]loxistatin acid to rat liver microsomal proteins by 75%. Unlike the rat, administration of loxistatin to hamsters caused neither hepatic injury nor hepatic GSH depletion even at a high dose (500 mg/kg). Both the distribution and covalent binding of radioactivity in the hamster liver were one-third of those in rats following [14C]loxistatin dosing. These results suggest that loxistatin causes species-specific hepatotoxicity and that, at least in part, some of the toxic effects of loxistatin are mediated by the nonenzymatic covalent binding of loxistatin acid to thiol residues on cellular macromolecules.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cricetinae; Cysteamine; Cysteine Proteinase Inhibitors; Drug Interactions; Glutathione; In Vitro Techniques; Leucine; Liver Diseases; Male; Maleates; Mesocricetus; Necrosis; Protein Binding; Rats; Rats, Inbred Strains; Species Specificity; Tissue Distribution

Recently, we have reported that 3,5-dialkyl substitution of paracetamol, in contrast to 3-monoalkyl substitution, prevented the paracetamol-induced toxicity in freshly isolated rat hepatocytes without having any effect on its cytochrome P-450 mediated bioactivation to reactive N-acetyl-p-benzoquinone imines (NAPQI). In the present study the mechanism of this prevention of toxicity, with special emphasis on oxidative stress, was studied in more detail in freshly isolated rat hepatocytes, using paracetamol, 3-methyl-, 3,5-dimethyl-paracetamol, synthetic NAPQI and 3,5-dimethyl-NAPQI. 3-Methyl-paracetamol was found to induce glutathione (GSH) depletion, lipid-peroxidation and cytotoxicity in hepatocytes to the same extent as paracetamol. 3,5-Dimethyl-paracetamol, however, even when added in a ten-fold higher concentration when compared to paracetamol, did not induce any of these effects. Similar differences of toxicity were observed between NAPQI and 3,5-dimethyl-NAPQI; 3,5-dimethyl-NAPQI, in contrast to NAPQI, did not reduce protein thiol levels, did not induce GSH depletion, lipid-peroxidation nor cytotoxicity. Only after artificial depletion of GSH levels in the hepatocytes by DEM or BCNU, 3,5-dimethyl-NAPQI was cytotoxic. This effect was accompanied by depletion of protein thiol levels, but not by lipid-peroxidation. Addition of the disulfide reducing agent, dithiothreitol, prevented the artificially created cytotoxicity of 3,5-dimethyl-NAPQI. It is concluded that prevention of paracetamol-induced toxicity by 3,5-dialkyl substitution is primarily due to prevention of irreversible GSH-depletion, presumably caused by the inability of 3,5-dialkyl-NAPQI to conjugate with thiols. As a result, the GSH-dependent cellular defense mechanism against potential oxidative cellular injury by 3,5-dialkyl-NAPQI is left unimpaired. Our observations indicate that a compound, not capable of covalent binding to thiol groups of proteins, can induce toxicity solely as a result of protein thiol oxidation without inducing lipid-peroxidation.

Topics: Acetaminophen; Animals; Benzoquinones; Carmustine; Chemical and Drug Induced Liver Injury; Glutathione; Imines; Lipid Peroxides; Liver; Liver Diseases; Male; Maleates; Oxidation-Reduction; Quinones; Rats; Rats, Inbred Strains; Structure-Activity Relationship

The mechanisms of bromobenzene and iodobenzene hepatotoxicity in vivo were studied in mice. Both the intoxications caused a progressive decrease in hepatic glutathione content. In both instances liver necrosis was evident only when the hepatic glutathione depletion reached a threshold value (3.5-2.5 nmol/mg protein). The same threshold value was evident for the occurrence of lipid peroxidation. Similar results were obtained in a group of mice sacrificed 15-20 hours after the administration of diethylmaleate, a drug which is mainly conjugated with hepatic glutathione without previous metabolism. The correlation between lipid peroxidation and liver necrosis was much more significant than that between covalent binding and liver necrosis. This fact supports the view that lipid peroxidation is the major candidate for the liver cell death produced by bromobenzene intoxication. Moreover, a dissociation of liver necrosis from covalent binding was observed in experiments in which Trolox C (a lower homolog of vitamin E) was administered after bromobenzene poisoning. The treatment with Trolox C, in fact, almost completely prevented both liver necrosis and lipid peroxidation, while not changing at all the extent of the covalent binding of bromobenzene metabolites to liver protein.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bromobenzenes; Chemical and Drug Induced Liver Injury; Chromans; Glutathione; Iodobenzenes; Lipid Peroxides; Liver; Liver Diseases; Male; Maleates; Mice; Necrosis; Proteins; Rats; Rats, Inbred Strains

Cd has a strong affinity for sulfhydryl groups and is hepatotoxic. Thus, to further understand the mechanism of Cd-induced liver injury, the effect of increased and decreased hepatic glutathione (GSH) concentration on Cd-induced liver injury was examined. Liver GSH was lowered by pretreating rats with phorone (250 mg/kg, ip) or diethyl maleate (0.85 mg/kg, ip) 2 hr prior to challenge with various doses of Cd. Ten hours after Cd (1) 40-80% of the rats pretreated with phorone or diethyl maleate and challenged with 1.0-2.0 mg Cd/kg died whereas no mortality was observed in the control group; (2) plasma enzyme activities of alanine (ALT) and aspartate (AST) aminotransferase and sorbitol dehydrogenase (SDH) were markedly increased in phorone and diethyl maleate-pretreated rats challenged with Cd (0.7-2.0 mg/kg) versus control rats; and (3) moderate changes in liver histology were observed in corn oil pretreated and Cd challenged rats, while prior depletion of GSH potentiated histopathologic changes in liver produced by Cd alone. Another group of rats received cysteine (1.9 g/kg, po) 3 hr prior to injection of a lethal dose of Cd. Cysteine pretreatment increased liver GSH levels by 22% 3 hr after administration and attenuated Cd-induced liver injury as evidenced by marked decreases in plasma ALT, AST, and SDH activities. Pathological changes in liver were also reduced. These data indicate that liver reduced GSH concentration is important in modulating Cd-induced hepatotoxicity.

Topics: Alanine; Animals; Aspartic Acid; Cadmium Poisoning; Chemical and Drug Induced Liver Injury; Cysteine; Drug Synergism; Glutathione; Ketones; L-Iditol 2-Dehydrogenase; Liver; Liver Diseases; Male; Maleates; Rats; Rats, Inbred Strains; Transaminases; Triglycerides

Exposure of hyperthyroid rats to halothane results in a centrilobular necrosis of the liver and an 11-fold increase in serum glutamate-pyruvate transaminase (SGPT) levels. These effects are not seen in euthyroid animals. Paradoxically, administration of diethylmaleate to hyperthyroid rats significantly decreased the levels of hepatic glutathione and blocked the halothane-induced hepatic necrosis as well as decreased the elevation of SGPT. In contrast, pretreatment of animals with N-acetylcysteine, an intracellular sulfhydryl repletor , significantly increased the severity of the halothane-induced hepatic necrosis and increased the elevation of SGPT. Similarly, cysteamine, another intracellular sulfhydryl repletor , also exacerbated halothane-induced liver injury. Halothane-induced hepatotoxicity is at least in part apparently regulated by cellular glutathione levels. Paradoxically, glutathione seems to be involved in the bioactivation rather than the detoxification of halothane.

Topics: Acetylcysteine; Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Glutathione; Halothane; Hyperthyroidism; Liver; Male; Maleates; Rats; Sulfhydryl Compounds; Time Factors; Triiodothyronine

The protective effect of N-acetylcysteine against the toxicity of paracetamol, acrolein, and paraquat was investigated using isolated hepatocytes as the experimental system. N-acetylcysteine protects against paracetamol toxicity by acting as a precursor for intracellular glutathione. N-acetylcysteine protects against acrolein toxicity by providing a source of sulfhydryl groups, and is effective without prior conversion. Paraquat toxicity can be decreased by coincubating the cells with N-acetylcysteine, but the mechanism for the protective effect is not as clear in this instance. It is probable that N-acetylcysteine protects against paraquat toxicity by helping to maintain intracellular glutathione levels.

Topics: Acetaminophen; Acetone; Acetylcysteine; Acrolein; Aldehydes; Amino Acids; Animals; Cell Survival; Chemical and Drug Induced Liver Injury; Glutathione; Liver; Male; Maleates; Paraquat; Phenobarbital; Rats; Rats, Inbred Strains

Increased activities of liver glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (6PGD, EC 1.1.1.44) in the pentose phosphate cycle were accompanied with a depletion of reduced glutathione (GSH) following an intragastric administration of carbon tetrachloride (CCl4) to rats. Oxidized glutathione (GSSG) also decreased remarkably, keeping the GSSG: GSH ratio constant. No significant alteration of glutathione reductase (EC 1.6.4.2.), glutathione peroxidase (EC 1.11.1.9) and malic enzyme (EC 1.1.1.40) activities in the supernatant and gamma-glutamyl transpeptidase (gamma-GTP, EC 2.3.2.2) activity in the homogenate of the injured liver were observed. Furthermore, no marked difference in the GSH-synthesizing activity was found between control and CCl4-intoxicated liver. An intraperitoneal injection of GSH produced a significant increase in liver GSH content in control rats but not in CCl4-treated rats; G6PD activity was not affected. Intraperitoneal injections of diethylmaleate resulted in continuously diminished levels of liver GSH without any alteration of liver G6PD activity. In vitro disappearance of GSH added to the liver homogenate from CCl4-treated rats occurred enzymatically and could not be prevented by the addition of a NADPH-generating system. The results suggest that increased G6PD activity in CCl4-injured liver does not play an important role in the maintenance of glutathione in the reduced form and that the decreased GSH content in the injured liver might be caused by enhanced GSH catabolism not due to gamma-GTP.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Glucosephosphate Dehydrogenase; Glutathione; Liver; Male; Maleates; Oxidation-Reduction; Phosphogluconate Dehydrogenase; Rats; Rats, Inbred Strains

Topics: Animals; Chemical and Drug Induced Liver Injury; Cyclohexanes; Cyclohexanones; Glutathione; Lung Diseases; Male; Maleates; Mice; Mice, Inbred BALB C; Oils, Volatile; Terpenes; Time Factors

Topics: Aminopyrine N-Demethylase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Glutathione; Kinetics; Liver; Male; Maleates; Microsomes, Liver; Nitroanisole O-Demethylase; Rats

Topics: Animals; Chemical and Drug Induced Liver Injury; Depression, Chemical; Glutathione; Iodoacetamide; Lipid Peroxides; Liver; Male; Maleates; Rats; Time Factors; Vanadium

Topics: Animals; Antimetabolites; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cytosol; Glutathione Transferase; In Vitro Techniques; Liver; Maleates; Rats; Time Factors

Topics: Alanine Transaminase; Alcohols; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Drug Synergism; Fasting; Glutathione; Liver; Male; Maleates; Rats

Topics: Animals; Chemical and Drug Induced Liver Injury; Cysteine; Ethylenes; Hydrocarbons, Chlorinated; L-Iditol 2-Dehydrogenase; Liver; Male; Maleates; Organ Size; Polychlorinated Biphenyls; Rats; Time Factors; Trichloroepoxypropane; Vinyl Chloride; Vinyl Compounds