glycogen and Chemical-and-Drug-Induced-Liver-Injury

Topics: Alcoholic Intoxication; Alcoholism; Animals; Chemical and Drug Induced Liver Injury; Ethanol; Fats; Fatty Liver; Glucose; Glycogen; Hepatomegaly; Humans; Lipid Metabolism; Liver; Liver Cirrhosis; Microsomes, Liver; Social Problems

Ground-glass (GG) hepatocytes are classically associated with chronic hepatitis B (HBV) infection, storage disorders, or cyanamide therapy. In a subset of cases, an exact etiology cannot be identified. In this study, we sought to characterize the clinical, histological, and ultrastructural findings associated with HBV-negative GG hepatocytes. Our institutional laboratory information system was searched from 2000 to 2019 for all cases of ground-glass hepatocytes. Ten liver biopsies with GG hepatocellular inclusions and negative HBV serology, no known history of storage disorders, or cyanamide therapy were reviewed. Half of the patients had history of organ transplantation and/or malignancy. These patients took on average 8.1 medications (range: 3-14) with the most common medications being immunosuppressive and health supplements. Histologically, GG hepatocytes show either peri-portal or centrizonal distribution. The inclusions are PAS-positive and diastase sensitive. Electron microscopy showed intracytoplasmic granular inclusions with low electron density, consistent with unstructured glycogen. In summary, GG hepatocytes are a rare finding in liver biopsies, but are more common in patients with hepatitis B. They can also be seen in HBV-negative patients who have polypharmacy. In these cases, they are the result of unstructured glycogen accumulation putatively due to altered cell metabolism.

Topics: Adult; Aged; Biopsy; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Child, Preschool; Cyanamide; Cytoplasm; Dietary Supplements; Female; Glycogen; Glycogen Storage Disease; Hepatitis B, Chronic; Hepatocytes; Humans; Immunosuppressive Agents; Inclusion Bodies; Liver; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Polypharmacy

p-Nitrophenol (PNP) is the main end product of organophosphorus insecticides and a derivative of diesel exhaust particles. In addition to its unfavorable impact on reproductive functions in both genders, it also has various harmful physiological effects including lung cancer and allergic rhinitis. The identification of the cellular readout that functions in metabolic pathway perpetuation is still far from clear. This research aimed to study the impact of chronic PNP exposure on the health condition of the liver in Japanese quails. Quails were exposed to different concentrations of PNP as follows: 0.0 (control), 0.01mg (PNP/0.01), 0.1mg (PNP/0.1), and 1mg (PNP/1) per kg of body weight for 2.5 months through oral administration. Liver and plasma samples were collected at 1.5, 2, and 2.5 months post-treatment for biochemical, histopathology, and immunohistochemistry assessment. The plasma aspartate aminotransferase (AST) level was assessed enzymatically. The livers were collected for histopathology, glycogen accumulation, proliferating cell nuclear antigen (PCNA), and apoptosis assessment. Our results revealed an irregularity in body weight due to the long-term exposure of PNP with a significant reduction in liver weight. PNP treatment caused histopathological alterations in the hepatic tissues which increased in severity by the long-term exposure. The low dose led to mild degeneration with lymphocytic infiltration, while the moderate dose has a congestion effect with some necrosis; meanwhile severe hepatocyte degeneration and RBCs hemolysis were noticed due to high dose of PNP. Glycogen accumulation increased in hepatocytes by prolonged exposure to p-Nitrophenol with the highest intensity in the group treated by the high dose. Moderate and high doses of PNP resulted in a significant increase in apoptosis and hepatocytes' proliferation at the different time points after treatment. This increase is markedly notable and maximized at 2.5 months post-treatment. The damage occurred in a time-dependent manner. These changes reflected on the plasma hepatic enzyme AST that was clearly increased at 2.5 months of exposure. Therefore, it could be concluded that PNP has profound toxic effects on the liver in cellular level. Taking into consideration the time and dose factors, both have a synergistic effect on the accumulation of glycogen, apoptosis, and cellular proliferation, highlighting the power of cellular investigation which will potentially open the door for earl

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Coturnix; Female; Glycogen; Humans; Liver; Male; Nitrophenols

The purpose of this study was to determine the effects of single and combined administrations of deoxynivalenol (DON) and zearalenone (ZEN) on the histology and ultrastructure of pig liver. The study was performed on immature gilts, which were divided into four equal groups. Animals in the experimental groups received DON at a dose of 12 μg/kg body weight (BW) per day, ZEN at 40 μg/kg BW per day, or a mixture of DON (12 μg/kg BW per day) and ZEN (40 μg/kg BW). The control group received vehicle. The animals were killed after 1, 3, and 6 weeks of experiment. Treatment with mycotoxins resulted in several changes in liver histology and ultrastructure, including: (1) an increase in the thickness of the perilobular connective tissue and its penetration to the lobules in gilts receiving DON and DON + ZEN; (2) an increase in the total microscopic liver score (histology activity index (HAI)) in pigs receiving DON and DON + ZEN; (3) dilatation of hepatic sinusoids in pigs receiving ZEN, DON and DON + ZEN; (4) temporary changes in glycogen content in all experimental groups; (5) an increase in iron accumulation in the hepatocytes of gilts treated with ZEN and DON + ZEN; (6) changes in endoplasmic reticulum organization in the hepatocytes of pigs receiving toxins; (7) changes in morphology of Browicz-Kupffer cells after treatment with ZEN, DON, and DON + ZEN. The results show that low doses of mycotoxins used in the present study, even when applied for a short period, affected liver morphology.

Topics: Animals; Chemical and Drug Induced Liver Injury; Female; Glycogen; Iron; Liver; Necrosis; Sus scrofa; Trichothecenes; Zearalenone

For the clinical application of stem cell therapy, functional enhancement is needed to increase the survival rate and the engraftment rate. The purpose of this study was to investigate functional enhancement of the paracrine effect using stem cells and hepatocyte-like cells and to minimize stem cell homing by using a scaffold system in a liver disease model.. A microporator was used to overexpress Foxa2 in adipose tissue-derived stem cells (ADSCs), which were cultured in a poly(lactic-co-glycolic acid) (PLGA) scaffold. Later, the ADSCs were cultured in hepatic differentiation medium for 2 weeks by a 3-step method. For. Foxa2-overexpressing ADSCs showed greater increases in hepatocyte-specific gene markers (alpha fetoprotein [AFP], cytokeratin 18 [CK18], and albumin), cytoplasmic glycogen storage, and cytochrome P450 expression than cells that underwent the conventional differentiation method.. Foxa2-overexpressing ADSCs applied in a scaffold system enhanced hepatocyte-like differentiation and attenuated acute liver damage in an acute liver injury model without homing effects.

Topics: Albumins; alpha-Fetoproteins; Animals; Biocompatible Materials; Cell Differentiation; Cells, Cultured; Chemical and Drug Induced Liver Injury; Connexins; Cytochrome P-450 Enzyme System; Dipeptidyl Peptidase 4; Electroporation; Gap Junction beta-1 Protein; Glycogen; Hepatocyte Nuclear Factor 3-beta; Hepatocytes; Keratin-18; Liver; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Nude; Plasmids; Polylactic Acid-Polyglycolic Acid Copolymer; Thioacetamide; Tissue Scaffolds

This study was designed to investigate whether the mice treated with triptolide (TP) could disrupt the liver immune homeostasis, resulting in the inability of the liver to eliminate the harmful response induced by lipopolysaccharide (LPS). In addition, we explored whether apoptosis and necroptosis played a critical role in the progression of the hepatotoxicity induced by TP-LPS co-treatment.. Female C57BL/6 mice were continuously administrated with two different doses of TP (250 μg/kg and 500 μg/kg) intragastrically for 7 days. Subsequently, a single dose of LPS (0.1 mg/kg) was injected intraperitoneally to testify whether the liver possesses the normal immune function to detoxicate the exogenous pathogen's stimulation. To prove the involvement of apoptosis and necroptosis in the liver damage induced by TP-LPS co-treatment, apoptosis inhibitor Z-VAD-FMK (FMK) and necroptosis inhibitor necrostatin (Nec-1) were applied before the stimulation of LPS to diminish the apoptosis and necroptosis respectively.. TP or LPS alone did not induce significant liver damage. However, compared with TP or LPS treated mice, TP-LPS co-treatment mice showed obvious hepatotoxicity with a remarkable elevation of serum ALT and AST accompanied by abnormal bile acid metabolism, a depletion of liver glycogen storage, aberrant glucose metabolism, an up-regulation of inflammatory cell infiltration, and an increase of apoptosis and necroptosis. Intraperitoneal injection of FMK or Nec-1 could counteract the toxic reactions induced by TP-LPS co-treatment.. TP could disrupt the immune response, resulting in hypersensitivity of the liver upon LPS stimulation, ultimately leading to abnormal liver function and cell death. Additionally, apoptosis and necroptosis played a vital role in the development of liver damage induced by TP-LPS co-treatment.

Topics: Alanine Transaminase; Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Aspartate Aminotransferases; Bile Acids and Salts; Caspase Inhibitors; Chemical and Drug Induced Liver Injury; Diterpenes; Dose-Response Relationship, Drug; Epoxy Compounds; Female; Glucose; Glycogen; Imidazoles; Immunologic Factors; Indoles; Lipopolysaccharides; Liver; Mice, Inbred C57BL; Necrosis; Phenanthrenes; Signal Transduction

Although sertraline is widely prescribed as relatively safe antidepressant drug, hepatic toxicity was reported in some patients with sertraline treatment. The present study was conducted to investigate the morphometric, hepatotoxicity, and change in gene expression of drug metabolizing enzymes. Male healthy adult rabbits (Oryctolagus cuniculus) ranging from 1050 to 1100 g were exposed to oral daily doses of sertraline (0, 1, 2, 4, 8 mg/kg) for 9 weeks. The animals were subjected to morphometric, hepatohistological, histochemical and quantitative real-time polymerase chain reaction analyses. Sertraline chronic exposure induced morphometric changes and provoked histological and histochemical alterations including: hepatocytes hydropic degeneration, necrosis, nuclear alteration, sinusoidal dilation, bile duct hyperplasia, inflammatory cells infiltration, portal vessel congestion, Kupffer cells hyperplasia, portal fibrosis and glycogen depletion. In addition, the gene expression of drug and arachidonic acid metabolizing enzymes were reduced significantly (p value <0.05). The most affected genes were cyp4a12, ephx2, cyp2d9 and cyp1a2, demonstrating 5 folds or more down-regulation. These findings suggest that chronic sertraline treatment induced toxic histological alterations in the hepatic tissues and reduced the gene expression of drug metabolizing enzymes. Patients on chronic sertraline treatment may be on risk of hepatotoxicity with reduced capacity to metabolize drugs and fatty acids.

Topics: Animals; Antidepressive Agents; Chemical and Drug Induced Liver Injury; Chronic Disease; Cytochrome P-450 Enzyme System; Gene Expression Regulation; Glucose Transporter Type 1; Glucuronosyltransferase; Glycogen; Liver; Male; Rabbits; Selective Serotonin Reuptake Inhibitors; Sertraline; Urinary Bladder

Dinoseb is a highly toxic pesticide of the dinitrophenol group. Its use has been restricted, but it can still be found in soils and waters in addition to being a component of related pesticides that, after ingestion by humans or animals, can originate the compound by enzymatic hydrolysis. As most dinitrophenols, dinoseb uncouples oxidative phosphorylation. In this study, distribution, lipid bilayer affinity and kinetics of the metabolic effects of dinoseb were investigated, using mainly the isolated perfused rat liver, but also isolated mitochondria and molecular dynamics simulations. Dinoseb presented high affinity for the hydrophobic region of the lipid bilayers, with a partition coefficient of 3.75×10

Topics: 2,4-Dinitrophenol; Adenosine Triphosphate; Animals; Biological Transport; Chemical and Drug Induced Liver Injury; Energy Metabolism; Fructose; Gluconeogenesis; Glycogen; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Kinetics; Lactic Acid; Lipid Bilayers; Liver; Male; Membrane Lipids; Mitochondria, Liver; Models, Biological; Molecular Dynamics Simulation; Oxidative Phosphorylation; Pesticides; Rats, Wistar; Risk Assessment; Urea

Glycogenic hepatopathy (GH) is an underdiagnosed complication of uncontrolled type 1 diabetes mellitus (T1DM). It appears as an acute relapsing hepatitis with reversible transaminase elevations secondary to excessive hepatic glycogen accumulation. Patients are often asymptomatic but can present with abdominal pain, nausea and vomiting. Physical examination shows hepatomegaly without splenomegaly. GH is diagnosed by biopsy as it is clinically indistinguishable from non-alcoholic fatty liver disease (NAFLD), a more common cause of hepatic dysfunction in diabetics. Here we describe a case of GH in a patient with uncontrolled type 1 diabetes whose clinical course was complicated by drug-induced liver injury. The patient initially presented with diabetic ketoacidosis and had a mild transaminitis, thought to be due to NAFLD. She developed profound transaminase elevations while receiving treatment with newer antipsychotic medications for her bipolar disorder. Liver biopsy showed evidence of resolving glycogenic hepatopathy with signs of drug-induced liver injury. This case report reviews the pathology and pathogenesis of GH and reminds the clinician to keep GH within the differential diagnosis for severe transaminitis in a patient with type 1 diabetes mellitus.

Topics: Abdominal Pain; Antipsychotic Agents; Biopsy; Bipolar Disorder; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Diagnosis, Differential; Dibenzocycloheptenes; Female; Glycogen; Hepatomegaly; Heterocyclic Compounds, 4 or More Rings; Humans; Liver; Magnetic Resonance Imaging; Young Adult

Zinc oxide nanoparticles (ZnO NPs) are widely used in industry and cosmetic products with promising investment in medical diagnosis and treatment. However, these particles may reveal a high potential risk for human health with no information about hepatotoxicity that might be associated with their exposure. The present work was carried out to investigate the histological and histochemical alterations induced in the hepatic tissues by naked 35nm ZnO NPs. Male Wistar albino rats were exposed to ZnO NPs at a daily dose of 2mg/kg for 21days. Liver biopsies from all rats under study were subjected to histopathological examinations. In comparison with the control rats, the following histological and histochemical alterations were demonstrated in the hepatic tissues of rats exposed to ZnO NPs: sinusoidal dilatation, Kupffer cells hyperplasia, lobular and portal triads inflammatory cells infiltration, necrosis, hydropic degeneration, hepatocytes apoptosis, anisokaryosis, karyolysis, nuclear membrane irregularity, glycogen content depletion and hemosidrosis. The findings of the present work might indicate that ZnO NPs have potential oxidative stress in the hepatic tissues that may affect the function of the liver. More work is needed to elucidate the toxicity and pathogenesis of zinc oxide nanoparticles on the vital organs.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Glycogen; Hemosiderosis; Hepatocytes; Kupffer Cells; Liver; Male; Nanoparticles; Necrosis; Particle Size; Rats, Wistar; Surface Properties; Zinc Oxide

The aim of this study was to investigate histological changes in hepatic tissue and effects of pentoxifylline (PTX) and caffeic acid phenethyl ester (CAPE) on these changes using histochemical and biochemical methods in rats, in which hepatitis was established by D-galactosamine (D-GAL). Rats were divided into five groups as follows: control group, D-GAL (24 h) group, D-GAL group, d-GAL + PTX group, and D-GAL + CAPE group. In histological evaluations, the control group showed normal appearance of the liver cells. However in the d-GAL groups, focal areas consisting of inflammatory, necrotic, and apoptotic cells were detected in parenchyma. Glycogen loss was observed in the hepatocytes localized at the periphery of lobule. It was found that number of mast cells of portal areas were significantly higher in D-GAL groups compared with other groups (p = 0.0001). In addition, the number of cells with positive staining by Ki-67 and caspase-3 were significantly increased in GAL groups compared with the control group (p = 0.0001). In biochemical analysis, there was an increase in malondialdehyde and myeloperoxidase levels, while a decrease was observed in glutathione level and glutathione peroxidase activity in groups treated with d-GAL compared with the control group. On the other hand, it was seen that, in the groups treated with D-GAL, histological and biochemical injuries in the liver were reduced by administration of PTX and CAPE. In this study, we demonstrated the ameliorative effects of PTX and CAPE on D-GAL-induced liver injury.

Topics: Animals; Caffeic Acids; Caspase 3; Chemical and Drug Induced Liver Injury; Galactosamine; Glycogen; Ki-67 Antigen; Liver; Male; Malondialdehyde; Mast Cells; Pentoxifylline; Peroxidase; Phenylethyl Alcohol; Rats; Rats, Wistar

We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 µg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1β, -2, -4, -6, and -10, as well as TNF-α and IFN-γ, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNA-Seq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.

Topics: Animals; Ascorbic Acid; Cellular Reprogramming; Chemical and Drug Induced Liver Injury; Collagen; Cytokines; Dose-Response Relationship, Drug; Energy Metabolism; Extracellular Matrix; Female; Gene Expression Regulation; Glucose; Glycogen; Inflammation Mediators; Liver; Liver Cirrhosis; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Polychlorinated Dibenzodioxins; Proline; Time Factors; Transcriptome

Cyanobacterial blooms threaten human health as well as the population of other living organisms in the aquatic environment, particularly due to the production of natural toxic components, the cyanotoxin. So far, the most studied cyanotoxins are microcystins (MCs). In this study, the hepatic alterations at histological, proteome and transcriptome levels were evaluated in female and male medaka fish chronically exposed to 1 and 5 μg L

Topics: Animals; Bacterial Toxins; Cell Extracts; Chemical and Drug Induced Liver Injury; Circadian Rhythm; Down-Regulation; Female; Fish Diseases; Glycogen; Lipid Metabolism; Liver; Male; Microcystins; Microcystis; Oryzias; Oviparity; Protein Biosynthesis; Proteome; Reproduction; Transcriptome

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10g/kg DEG and blood, kidney and liver tissues were collected at 48h. Both rat strains treated with 10g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10g/kg DEG, but no DGA was present at 2 or 5g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments.

Topics: Acidosis; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Chemical and Drug Induced Liver Injury; Creatine; Dose-Response Relationship, Drug; Ethylene Glycols; Glycogen; Glycolates; Kidney; Kidney Diseases; Liver; Male; Rats, Inbred F344; Rats, Wistar

The increasing use of organophosphorus pesticides in the environment constitutes an ecotoxicological hazard especially for humans and non-target animals. Hereby, we analyzed the toxic effects of malathion on the histological structure of liver and biochemical parameters in male rats. Three groups received daily different amounts of malathion: 1/1000, 1/100, and 1/10 LD50 for 30 days. The weights of treated rat's liver have increased. Analyzed tissues showed centrilobular and sinusoidal congestion, hepatocyte hypertrophy, cellular vacuolization, anucleated hepatocytes, depletion of organelles affecting the majority of cells, and presence of necrotic foci into the hepatic parenchyma. Histological sections of the liver showed important hepatocyte glycogen storage. We conclude that malathion stimulates the filing of glycogen in a dose-dependent manner. Biochemical parameters showed that alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) levels increased in the treated groups when the level of total protein decreased in intoxicated groups.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Biomarkers; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Environmental Pollutants; gamma-Glutamyltransferase; Glycogen; Hepatocytes; Humans; L-Lactate Dehydrogenase; Liver; Malathion; Male; Rats; Rats, Wistar

This study investigates the protective effect of betanin against liver injury induced by carbon tetrachloride (CCl4) in common carp (Cyprinus carpio L.). The fish were treated with 1, 2, and 4 % betanin in fodder throughout the experiment. After 20 days of treatment, the fish were intraperitoneally injected with 20 % (v/v in peanut oil) CCl4 at a volume of 0.5 mL/kg body weight. The fish were killed 3 days after CCl4 intoxication, and then, histological and biochemical assays were performed. Results showed that CCl4-induced liver CYP2E1 activity, oxidative stress, and injury, as indicated by the depleted glycogen storage, increased serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) activities and liver histological damage. Compared with the CCl4 control group, the betanin-treated groups exhibited reduced CYP2E1 activity, decreased malondialdehyde level, increased liver antioxidative capacity (increased glutathione level and superoxide dismutase and catalase activities), increased liver glycogen storage, and reduced serum AST/ALT activities, with significant differences in the 2 and 4 % groups (p < 0.05). Histological assay further confirmed the protective effect of betanin. In conclusion, betanin attenuates CCl4-induced liver damage in common carp. Moreover, the inhibition of CYP2E1 activity and oxidative stress may have significant roles in the protective effect of betanin.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Betacyanins; Carbon Tetrachloride Poisoning; Carps; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Glycogen; Liver; Oxidative Stress; Random Allocation

Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage.

Topics: Acetaminophen; Animals; Benzoquinones; Chemical and Drug Induced Liver Injury; Gene Expression Regulation; Glutathione; Glycogen; Hepatocytes; Imines; Inactivation, Metabolic; Lipogenesis; Liver; Mice; Thioredoxin Reductase 1; Thioredoxins

The action of an Agaricus blazei aqueous extract pretreatment on paracetamol injury in rats was examined not only in terms of the classical indicators (e.g., levels of hepatic enzymes in the plasma) but also in terms of functional and metabolic parameters (e.g., gluconeogenesis). Considering solely the classical indicators for tissue damage, the results can be regarded as an indication that the A. blazei extract is able to provide a reasonable degree of protection against the paracetamol injury in both the hepatic and brain tissues. The A. blazei pretreatment largely prevented the increased levels of hepatic enzymes in the plasma (ASP, ALT, LDH, and ALP) and practically normalized the TBARS levels in both liver and brain tissues. With respect to the functional and metabolic parameters of the liver, however, the extract provided little or no protection. This includes morphological signs of inflammation and the especially important functional parameter gluconeogenesis, which was impaired by paracetamol. Considering these results and the long list of extracts and substances that are said to have hepatoprotective effects, it would be useful to incorporate evaluations of functional parameters into the experimental protocols of studies aiming to attribute or refute effective hepatoprotective actions to natural products.

Topics: Acetaminophen; Administration, Oral; Agaricus; Alanine; Animals; Antioxidants; Biomarkers; Brain; Brain Diseases; Chemical and Drug Induced Liver Injury; Complex Mixtures; Enzyme Assays; Glucose; Glycogen; Lactic Acid; Lipid Metabolism; Liver; Male; Oxidative Stress; Rats; Rats, Wistar; Time Factors

Monosodium glutamate (MSG) is a commonly used food enhancer. Glutamate is used as food additive for enhancing the "meat flavor" of food and gives a particular taste named "umami". In this study, we evaluated the effect of vitamin C on monosodium glutamate induced rat liver injury. This study was divided into 3 groups: group 1 received a diet containing 0.9% NaCl; group 2 received diet containing MSG 6 mg/g/b.w.; and group 3 received a diet containing 6 mg/g/b.w. followed by vitamin C (500 mg/kg/b.w.) for 45 days. The resulting changes were detected using histological, histochemical, ultrastructural, and immuohistochemical analysis. Severe alterations were recorded including dilatations of the central veins; severe cyto-architectural distortions of the hepatocytes; marked reduction in both carbohydrates and proteins; vacuolated cytoplasm, swollen mitochondria and vesiculated rough endoplasmic reticulum with picknotic nuclei; in addition to significant variation in the expression of ki-67 and p53 proteins. The data obtained from this study showed the improvements in the pathological architecture of the liver after treatment with vitamin C. The present data point to the ameliorative effect of vitamin C against MSG induced liver injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Chemical and Drug Induced Liver Injury; Collagen; Disease Models, Animal; Glycogen; Immunohistochemistry; Ki-67 Antigen; Liver; Male; Microscopy, Electron, Transmission; Rats; Sodium Glutamate; Tumor Suppressor Protein p53

Transplantation and drug discovery programs for liver diseases are hampered by the shortage of donor tissue. While recent studies have shown that hepatic cells can be derived from human embryonic stem cells (hESCs), few cases have shown selective enrichment of hESC-derived hepatocytes and their integration into host liver tissues. Here we demonstrate that the dissociation and reaggregation procedure after an endodermal differentiation of hESC produces spheroids mainly consisted of cells showing hepatic phenotypes in vitro and in vivo. A combined treatment with Wnt3a and bone morphogenic protein 4 efficiently differentiated hESCs into definitive endoderm in an adherent culture. Dissociation followed by reaggregation of these cells in a nonadherent condition lead to the isolation of spheroid-forming cells that preferentially expressed early hepatic markers from the adherent cell population. Further differentiation of these spheroid cells in the presence of the hepatocyte growth factor, oncostatin M, and dexamethasone produced a highly enriched population of cells exhibiting characteristics of early hepatocytes, including glycogen storage, indocyanine green uptake, and synthesis of urea and albumin. Furthermore, we show that grafted spheroid cells express hepatic features and attenuate the serum aspartate aminotransferase level in a model of acute liver injury. These data suggest that hepatic progenitor cells can be enriched by the spheroid formation of differentiating hESCs and that these cells have engraftment potential to replace damaged liver tissues.

Topics: Albumins; Animals; Biomarkers; Bone Morphogenetic Protein 4; Carbon Tetrachloride; Cell Culture Techniques; Cell Differentiation; Chemical and Drug Induced Liver Injury; Dexamethasone; Embryonic Stem Cells; Endoderm; Glycogen; Graft Survival; Hepatocyte Growth Factor; Hepatocytes; Humans; Mice; Mice, Nude; Oncostatin M; Spheroids, Cellular; Transplantation, Heterologous; Urea; Wnt3A Protein

The effects of montelukast against methotrexate-induced liver damage were investigated. 35 Wistar albino female rats were divided into 5 groups as follows: group I: control; group II: montelukast (ML); group III: methotrexate (Mtx); group IV: montelukast treatment after methotrexate application (Mtx + ML); group V: montelukast treatment before methotrexate application (ML + Mtx). At the end of the experiment, the liver tissues of rats were removed. Malondialdehyde (MDA), myeloperoxidase (MPO), and reduced glutathione levels were determined from liver tissues. In addition, the liver tissues were examined histologically. MDA and MPO levels of Mtx group were significantly increased when compared to control group. In Mtx + ML group, these parameters were decreased as compared to Mtx group. Mtx injection exhibited major histological alterations such as eosinophilic staining and swelling of hepatocytes. The glycogen storage in hepatocytes was observed as decreased by periodic acid schiff staining in Mtx group as compared to controls. ML treatment did not completely ameliorate the lesions and milder degenerative alterations as loss of the glycogen content was still present. It was showed that montelukast treatment after methotrexate application could reduce methotrexate-induced experimental liver damage.

Topics: Acetates; Animals; Chemical and Drug Induced Liver Injury; Cyclopropanes; Drug Evaluation, Preclinical; Female; Glutathione; Glycogen; Hepatocytes; Liver; Malondialdehyde; Methotrexate; Oxidative Stress; Periodic Acid-Schiff Reaction; Peroxidase; Quinolines; Rats; Rats, Wistar; Sulfides

The introduction of polyprenols isolated from fir (Abies) tree in male rats weighing 170 - 180 g with alcohol-induced hepatitis favored reduction in hepatocyte cytolysis and cholestasis and led to an improvement of the protein- and glycogen-synthesizing function of liver. A clear tendency to normalization of the maintenance of total lipids, triglycerides and phospholipids and the inhibition of lipid peroxidization processes in the damaged organ was observed. The introduction of Abies polyprenols also improved the process of bile secretion and its chemical composition.

Topics: Abies; Animals; Bile; Central Nervous System Depressants; Chemical and Drug Induced Liver Injury; Ethanol; Glycogen; Hepatocytes; Lipid Peroxidation; Male; Protein Biosynthesis; Rats; Silymarin; Terpenes

Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/-) mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2(-/-) mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.

Topics: Acetaminophen; Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Cholesterol Esters; Cytokines; DNA; Glycogen; Kinetics; Liver; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II; Spectroscopy, Fourier Transform Infrared

The purpose of this study was to investigate the potential acute and 28-day repeated oral toxicities of besifloxacin (BAF) in Wistar albino rats. In oral acute and repeated dose study, BAF was administered to both sex of rats, at dose levels of 0, 300, 600, 900 mg/kg/day and 0, 100, 200, 500 mg/kg/day, respectively. In the acute study, total white blood cell (WBC) (male, 43.74%; female, 42.60%) and total bilirubin (T-BIL) (male, 80%; female, 60%) were significantly increase, total protein (TP) (male, 23.24%; 27.80%) was significantly decreased, and significant incidence of pericholangitis (male, 83.33%; female, 75%) was shown in males and females of high-dose groups. In repeated oral dose toxicity study, similar type effects were also observed after serum hematological and serum biochemical analysis, whereas additionally sever hepatic injury and focal ulceration in gastric mucosa also observed in high dose groups of both sexes after histopathological analysis. However these toxic effects of besifloxacin were transient and reversible and no-observed adverse effect level (NOAEL) were 300 mg/kg/day for acute and 100 mg/kg/day for repeated dose toxicity study, respectively.

Topics: Achilles Tendon; Animals; Anti-Bacterial Agents; Azepines; Bilirubin; Blood Platelets; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Female; Fluoroquinolones; Glycogen; Joints; Leukocyte Count; Liver; Male; Photosensitivity Disorders; Rats; Rats, Wistar; Stomach Ulcer; Thrombocytosis; Toxicity Tests, Acute; Toxicity Tests, Subacute

Hepatocytes are an important research tool used for numerous applications. However, a short life span and a limited capacity to replicate in vitro limit the usefulness of primary hepatocyte cultures. We have hypothesized that in vivo priming of hepatocyte could make them more susceptible to growth factors in the medium for continuous proliferation in vitro. Here, a novel approach used to establish hepatocyte cell lines that included hepatocyte priming in vivo prior to culture with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet was attempted. The cell line grew in a monolayer while maintaining a granular cytoplasm and a round nucleus. Electron microscopy displayed hepatocyte-like features including mitochondria, glycogen granules, and the presence of bile canaliculi. This cell line expressed many mature hepatocyte-specific genes including albumin, alpha1-antitrypsin, glucose 6-phosphatase, and tyrosine aminotransferase. Functional characteristic of hepatocytes like the ability to store glycogen, lipid, and synthesis of urea is well demonstrated by this cell line. These cells demonstrated anchorage dependent growth properties in soft agar and did not form tumors after transplantation into nude mice. This cell line can be sustained in culture for more than 100 passages (>1.5 years) without undergoing noticeable morphological changes or transformation. This novel method resulted in the establishment of an immortal, non-transformed hepatocyte cell line with functional characteristics that may aid research of cell metabolism, toxicology, and hepatocyte transplantation.

Topics: Albumins; Animals; Cell Line; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glucose-6-Phosphatase; Glycogen; Hepatocytes; Lipids; Liver; Male; Mice; Pyridines; Urea

Transforming growth factor-beta (TGF-beta) plays a pivotal role in liver fibrosis, because it activates hepatic stellate cells, stimulating extracellular matrix deposition. Cyclooxygenase-2 (COX-2) has been associated with TGF-beta because its inhibition decreases TGF-beta expression and collagen production in some cultured cell types.. The aim of this work was to evaluate the ability of celecoxib (a selective COX-2 inhibitor) to prevent and to reverse the liver fibrosis induced by CCl(4).. We established experimental groups of rats including vehicle and drug controls, damage induced by chronic CCl(4) administration and CCl(4) plus pharmacological treatment in both prevention and reversion models. We determined: alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, COX and metalloproteinase-2 and -9 activities, lipid peroxidation, glutathione levels, glycogen and collagen content and TGF-beta expression.. Celecoxib prevented and aided to the recovery of livers with necrotic and cholestatic damage. Celecoxib exhibited anti-oxidant properties by restoring the redox equilibrium (lipid peroxidation and glutathione levels). Glycogen was decreased by CCl(4), while celecoxib partially prevented and reversed this effect. Celecoxib inhibited COX-2 activity, decreased TGF-beta expression, induced metalloproteinase-2 activity and, consequently, prevented and reversed collagen accumulation.. Our findings indicate that celecoxib exerts strong antifibrogenic and fibrolytic effects in the CCl(4) model of cirrhosis.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Aspartate Aminotransferases; Carbon Tetrachloride; Celecoxib; Chemical and Drug Induced Liver Injury; Collagen; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; gamma-Glutamyltransferase; Glutathione; Glycogen; Liver; Liver Cirrhosis; Male; Malondialdehyde; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Time Factors; Transforming Growth Factor beta

The objective of the present study was to screen various solvent extracts of Polyalthia longifolia var. pendula (Annonaceae) leaf for anti-inflammatory activity and to evaluate the anti-inflammatory and hepatoprotective potency of the potent solvent extract. Successive extraction was performed with six different solvents, viz. petroleum ether, hexane, toluene, chloroform, acetone and methanol. Toluene, chloroform, acetone and methanol were used in acute inflammatory studies; the results revealed methanol as most potent extract. Hence three concentrations of methanolic extract (300, 600, 900 mg/kg) were used to evaluate its potential as an anti-inflammatory and hepatoprotective agent. Diclofenac sodium was used as the toxicant in hepatoprotective studies, in which various serum biochemical parameters and liver glycogen were assessed. The three concentrations of methanol showed anti-inflammatory activity comparable to that of the control (Diclofenac sodium). All the serum biochemical parameters studied revealed the hepatoprotective nature of the methanol extract, but a concentration effect was not observed. The results indicated that the methanolic extract of Polyalthia longifolia var. pendula leaf possesses significant anti-inflammatory and hepatoprotective activity. However, the appropriate effective concentration needs to be determined.

Topics: Acetone; Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Chloroform; Diclofenac; Dose-Response Relationship, Drug; Female; Glycogen; Hexanes; Liver; Liver Diseases; Male; Methanol; Plant Extracts; Plant Leaves; Polyalthia; Rats; Rats, Wistar; Toluene

The aim of this study was to investigate the effect of misoprostol, silymarin or the co-administration of misoprostol + silymarin on the carbon tetrachloride (CCl(4))-induced hepatic injury in rats. Misoprostol (10, 100, 1000 microg/kg), silymarin (25 mg/kg) or misoprostol (100 microg/kg) + silymarin (25 mg/kg) was given once daily orally simultaneously with CCl(4) and for 15 days thereafter. The results showed that misoprostol (10, 100 or 1000 microg/kg) conferred significant protection against the hepatotoxic actions of CCl(4) in rats, reducing serum alanine aminotransferase (ALT) levels by 24.7%, 42.6% and 49.4%, respectively compared with controls. Misoprostol, given at 100 or 1000 microg/kg, decreased aspartate aminotransferase (AST) by 28 and 43.6% and alkaline phosphatase (ALP) by 19.3% and 53.4% respectively. Meanwhile, silymarin reduced ALT, AST and ALP levels by 62.7%, 66.1% and 65.1% respectively. The co-administration of misoprostol (100 microg/kg) and silymarin (25 mg/kg) resulted in 61.4%, 66.1% and 57.5% reduction in ALT, AST and ALP levels respectively. Histopathological alterations and depletion of hepatocyte glycogen and DNA content by CCl(4) were markedly reduced after treatment with misoprostol, silymarin or misoprostol + silymarin. Image analysis of liver specimens revealed a marked reduction in liver necrosis; area of damage: 32.4%, 24% and 10.2% after misoprostol (10, 100 or 1000 microg/kg), 7.2% after silymarin and 10.9% after treatment with misoprostol 100 microg/kg + silymarin, compared with CCl(4) control group (46.7%). These results indicate that treatment with misoprostol protects against hepatocellular necrosis induced by CCl(4). This study suggests a potential therapeutic use for misoprostol in liver injury.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; DNA; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glycogen; Liver Diseases; Liver Function Tests; Male; Misoprostol; Necrosis; Protective Agents; Rats; Rats, Sprague-Dawley; Silymarin

Topics: 2,4-Dichlorophenoxyacetic Acid; Alcian Blue; Animals; Biomarkers; Cell Count; Chemical and Drug Induced Liver Injury; Fibronectins; Glial Fibrillary Acidic Protein; Glycogen; Hepatocytes; Herbicides; Liver; Male; Periodic Acid-Schiff Reaction; Rats; Rats, Wistar; Toxicity Tests

Cadmium is an environmental toxic metal implicated in human diseases. In the present study, the effect of diphenyl diselenide, (PhSe)(2), on sub-chronic exposure with cadmium chloride (CdCl(2)) was investigated in rats. Male adult Swiss albino rats received CdCl(2) (10 micromol/kg, orally) and (PhSe)(2) (5 micromol/kg, orally) for a period of 30 days. A number of parameters were examined as indicators of toxicity, including hepatic and renal damage, glucose and glycogen levels and markers of oxidative stress. Cadmium content, liver histology, delta-aminolevulinate dehydratase (delta-ALA-D) activity, metallothionein (MT) levels were also evaluated. Cadmium content determined in the tissue of rats exposed to CdCl(2) provides evidence that the liver is the major cadmium target where (PhSe)(2) acts. The concentration of cadmium in liver was about three fold higher than that in kidney, and (PhSe)(2) reduced about six fold the levels of this metal in liver of rats exposed. Rats exposed to CdCl(2) showed histological alterations abolished by (PhSe)(2) administration. (PhSe)(2) administration ameliorated plasma malondialdehyde (MDA) levels, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma-glutamyl transferase (GGT) activities increased by CdCl(2) exposure. Urea and bilirubin levels increased by CdCl(2) exposure were also reduced by (PhSe)(2). In conclusion, this study demonstrated that co-treatment with (PhSe)(2) ameliorated hepatotoxicity and cellular damage in rat liver after sub-chronic exposure with CdCl(2). The proposed mechanisms by which (PhSe)(2) acts in this experimental protocol are its antioxidant properties and its capacity to form a complex with cadmium.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Benzene Derivatives; Bilirubin; Blood Glucose; Cadmium; Cadmium Chloride; Chemical and Drug Induced Liver Injury; gamma-Glutamyltransferase; Glycogen; Kidney; L-Lactate Dehydrogenase; Liver; Liver Diseases; Male; Malondialdehyde; Organoselenium Compounds; Oxidative Stress; Porphobilinogen Synthase; Rats; Rats, Wistar; Sulfhydryl Compounds

The present study has been conducted to evaluate the curative effect of propolis extract, a honey bee-hive product, against acetaminophen (APAP) induced oxidative stress and dysfunction in liver and kidney. Animals were challenged with APAP (2 g/kg, p.o.) followed by treatment of propolis extract (100 and 200 mg/kg, p.o.) once only after 24 h. Release of transaminases, alkaline phosphatase, lactate dehydrogenase, and serum bilirubin were increased, whereas hemoglobin and blood sugar were decreased after APAP administration. Antioxidant status in both the liver and kidney tissues were estimated by determining the glutathione, malondialdehyde content and activities of the CYP enzymes, which showed significant alterations after APAP intoxication. In addition, activities of adenosine triphosphatase, acid phosphatase, alkaline phosphatase, and major cell contents (total protein, glycogen and cholesterol) were also altered due to APAP poisoning. Propolis extract successfully reversed the alterations of these biochemical variables at higher dose. Improvements in hepatorenal histoarchitecture were also consistent with biochemical observations. The results indicated that ethanolic extract of propolis has ability to reverse APAP-induced hepatorenal biochemical and histopathological alterations probably by increasing the antioxidative defense activities due to various phenolic compounds present in it.

Topics: Acetaminophen; Acid Phosphatase; Adenosine Triphosphatases; Alkaline Phosphatase; Animals; Antioxidants; Bilirubin; Blood Glucose; Chemical and Drug Induced Liver Injury; Cholesterol; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Female; Glutathione; Glycogen; Hemoglobins; Kidney; Kidney Diseases; L-Lactate Dehydrogenase; Liver; Liver Diseases; Malondialdehyde; Oxidative Stress; Propolis; Rats; Rats, Sprague-Dawley; Silymarin; Transaminases

Body temperature may critically affect mechanisms of liver injury in acetaminophen (APAP) hepatotoxicity. In addition, mild hypothermia is used to treat intracranial hypertension in human liver failure without detailed information on its effects on the injured liver itself. Therefore, we investigated the effects of body temperature on the progression of APAP-induced liver injury in mice.. Male C57BL6 mice treated with saline or APAP (300 mg/kg intraperitoneally) were maintained at normothermia (35.5-37.5 degrees C) by external warming or were allowed to develop mild hypothermia (32.0-35.0 degrees C) after 2 hours from APAP administration.. Mild hypothermia resulted in improved survival after APAP intoxication. Liver damage was reduced, as assessed histologically and by plasma alanine aminotransferase levels. Early effects of hypothermia included a reduction of hepatic congestion and improved recovery of glycogen stores. At later time points (8-12 hours), APAP-treated mice that were maintained at normothermia manifested increased hepatocyte apoptosis, as assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining and cleavage of poly(adenosine diphosphate-ribose) polymerase. Mild hypothermia did not affect the formation of APAP-protein adducts or the depletion of glutathione, nor did it abrogate hepatocyte DNA synthesis.. Mild hypothermia improved survival and attenuated liver injury and apoptosis in APAP-treated mice by reducing hepatic congestion and improving glycogen recovery without affecting hepatic regeneration. Results of the study underscore the need for a strict control of body temperature in animal models of liver failure and suggest that the benefits of mild hypothermia in liver failure may extend beyond those related to reduced cerebral complications.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Apoptosis; Body Temperature; Cell Count; Cell Division; Chemical and Drug Induced Liver Injury; DNA Adducts; Glutathione; Glycogen; Hemoglobins; Hepatocytes; Hypothermia, Induced; In Situ Nick-End Labeling; Liver; Male; Mice; Mice, Inbred C57BL; Necrosis; Severity of Illness Index; Survival Rate

High-fat diets and oxidative damage may contribute to the development of type 2 diabetes. Hypolipidaemic drugs and antioxidants were supposed to prevent the development of the disease. In this study, we investigated preventive effects of fenofibrate (200 mg kg(-1)), vitamin C (30 mg kg(-1)), combination of both in mice induced by streptozotocin (35 mg kg(-1)) and soluble lard (15 ml kg(-1)). The results showed the mice demonstrated hyperglycaemia and hypercholesterolaemia, visceral fat accumulation, and a slight increase in liver glycogen/triglyceride and oxidative stress within 60 days of treatment. Fenofibrate enhanced insulin sensitivity, improved glycaemic control, lowered serum triglycerides, reduced body and visceral fat weights, and decreased liver glycogen/lipid levels but showed hepatotoxicity in the mice. Vitamin C neither itself prevented nor enhanced preventive effects of fenofibrate on glucose and lipid metabolism but partly attenuated the hepatotoxicity of fenofibrate. These results suggest that fenofibrate inhibit development of type 2 diabetes induced by high-fat diets and oxidative stress. However, here, vitamin C just can serve as an adjunct to fenofibrate therapy against its hepatotoxicity. In the future study, we should investigate if higher dosage of vitamin C or other antioxidants would enhance preventive effects of fenofibrate in type 2 diabetes.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Chemical and Drug Induced Liver Injury; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Drug Therapy, Combination; Fenofibrate; Glycogen; Hypercholesterolemia; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Intra-Abdominal Fat; Liver; Liver Diseases; Male; Matrix Metalloproteinase 9; Mice; Oxidative Stress; Streptozocin; Triglycerides

Principal component analysis (PCA) has been applied to three nuclear magnetic resonance (NMR) spectral editing methods, namely, the Carr-Purcell-Meiboom-Gill spin-echo, diffusion editing, and skyline projection of a two-dimensional J-resolved spectrum, obtained from high-resolution magic-angle spinning NMR spectroscopy of liver tissues, to distinguish between control and hydrazine-treated rats. The effects of the toxin on rat liver biochemistry were directly observed and characterized by depleted levels of liver glycogen, choline, taurine, trimethylamine N-oxide, and glucose and by elevated levels of lipids and alanine. The highly unsaturated omega-3-type fatty acid was observed for the first time in hydrazine-treated rat liver. The contributions of the metabolites to the separation of control from dosed liver tissues varied depending on the type of spectral editing method used. We have shown that subtle changes in the metabolic profiles can be selectively amplified using a metabonomics approach based on the different NMR spectral editing techniques in conjunction with PCA.

Topics: Alanine; Animals; Chemical and Drug Induced Liver Injury; Choline; Glucose; Glycogen; Hydrazines; Lipids; Liver; Liver Diseases; Magnetic Resonance Spectroscopy; Male; Methylamines; Rats; Rats, Sprague-Dawley; Taurine; Toxins, Biological

Administration of aflatoxin B1 to rats (2 mg/kg intraperitoneally) caused significant increase in the activities of gamma-glutamyl transpeptidase, 5'-nucleotidase, acid phosphatase, acid ribonuclease as well as content of lipid peroxides in liver after six weeks. However, the activities of succinate dehydrogenase, glucose-6-phosphatase, catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and glutathione reductase in liver were decreased. The levels of glycogen and reduced glutathione were also decreased. There were significant elevations in the levels of serum transaminases, phosphatases (acid and alkaline), dehydrogenases (sorbitol, lactate and glutamate) and bilirubin following aflatoxin B1 administration. Picroliv (25 mg/kg/day orally for six weeks), an iridoid glycoside isolated from the roots and rhizomes of Picrorhiza kurroa, significantly prevented the biochemical changes induced by aflatoxin B1.

Topics: Aflatoxin B1; Animals; Chemical and Drug Induced Liver Injury; Cinnamates; Drug Interactions; Enzymes; Glutathione; Glycogen; Glycosides; Lipid Peroxidation; Liver; Male; Plant Extracts; Rats; Rats, Wistar; Vanillic Acid

The aim of the present study was to examine the effects of single and repeated administration of 3,4-methylenedioxyme-thamphetamine (MDMA, "ecstasy") on rat liver.. Animals were given an acute (20 mg/kg) and repeated (20 mg/kg, b.i.d., for 4 consecutive days) intraperitoneal dose of MDMA, and at various times after administration the hepatic and serum determinations were made.. The effect of acute MDMA administration included increased triglyceride and cholesterol levels and an increase in all enzyme activities 6 h post administration. The toxic effect of MDMA was also observed in other hepatic processes. Glycogen content showed a marked decrease, which was accompanied by a decrease in serum glucose levels. No significant changes in lipid peroxidation and hepatic GSH content were observed. In contrast, multiple MDMA administration produced some evidence of oxidative stress, namely, increased MDA content and decreased GSH content, a small decrease in liver glycogen at 3 h recovering 6 h post dose, no effect on blood glucose and increased AST and ALP activities but no effects on ALT activity. Seven days after the last MDMA injection a tendency towards recovery was shown.. Our results show that the liver toxicity caused by MDMA administration involves several mechanisms.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Blood Glucose; Chemical and Drug Induced Liver Injury; Cholesterol; Glutathione; Glutathione Transferase; Glycogen; Injections, Intraperitoneal; Lipid Peroxidation; Liver; Male; N-Methyl-3,4-methylenedioxyamphetamine; Oxidoreductases; Rats; Rats, Wistar; Serotonin Agents; Triglycerides

Three procedures were used to stimulate hepatocyte proliferation in the rat without reducing liver mass, resulting in a supplementary growth which differs from the regenerative growth observed after loss of liver mass by hepatectomy or toxic necrosis. They were: (a) the ingestion of cyproterone, a cytochrome P450 inducing drug (b) the injection of an irritant which provokes glycogenesis and synthesis of acute-phase proteins (c) the injection of albumin-bound bilirubin leading to elimination of glucuronated bilirubin in bile. This ensuing supplementary growth was studied in the rat under several conditions of hepatic proliferation: 1. In normal adult rats, in which hepatocyte proliferation is very low, the effect on proliferation was either weak or undetectable. 2. In suckling rats, with a rapid body and liver growth, all the stimulants provoked a synchronized wave of proliferation with a steep increase of the percentage of S-phase hepatocytes from 4.5% in controls to 15-30% in treated rats. This increase was followed by a compensatory period of low proliferation during which a treatment with a second stimulant was much less effective. 3. In 2/3 hepatectomized adult rats, the proliferation induced by cyproterone was higher than the spontaneous regenerative proliferation alone and additional to it during all of the regenerative process. The proliferation induced by acute inflammation was competitive with the synchronous spontaneous proliferation during the early period of synchronized proliferation following surgery, suggesting that both are similar acute responses. Differently, during the late period of lower and unsynchronized regenerative proliferation, the proliferation provoked by acute inflammation was additional to the spontaneous one. A stimulation of proliferation by injection of the albumin-bilirubin complex was observed during the late period after 2/3 hepatectomy. The highest level of stimulation occurred when the liver growth and the hepatocyte proliferation were already high. This suggests that these stimulants are not complete mitogenic stimuli and need cofactors which are present during the spontaneous growth or, alternatively, that the effect of stimulants is opposed by an inhibitory mechanism present in the adult rat.

Topics: Acute-Phase Reaction; Age Factors; Alanine Transaminase; Albumins; Androgen Antagonists; Animals; Animals, Suckling; Bilirubin; Caseins; Cell Division; Chelating Agents; Chemical and Drug Induced Liver Injury; Cyproterone; Energy Metabolism; Glycogen; Hepatectomy; Hepatocytes; Liver; Liver Diseases; Liver Regeneration; Male; Organ Size; Rats; Rats, Wistar

Although, diet restriction (DR) has been shown to substantially increase longevity while reducing or delaying the onset of age-related diseases, little is known about the mechanisms underlying the beneficial effects of DR on acute toxic outcomes. An earlier study (S. K. Ramaiah et al., 1998, Toxicol. Appl. Pharmacol. 150, 12-21) revealed that a 35% DR compared to ad libitum (AL) feeding leads to a substantial increase in liver injury of thioacetamide (TA) at a low dose (50 mg/kg, i.p.). Higher liver injury was accompanied by enhanced survival. A prompt and enhanced tissue repair response in DR rats at the low dose (sixfold higher liver injury) occurred, whereas at equitoxic doses (50 mg/kg in DR and 600 mg/kg in AL rats) tissue repair in AL rats was substantially diminished and delayed. The extent of liver injury did not appear to be closely related to the extent of stimulated tissue repair response. The purpose of the present study was to investigate the time course (0-120 h) of liver injury and liver tissue repair at the high dose (600 mg TA/kg, i.p., lethal in AL rats) in AL and DR rats. Male Sprague-Dawley rats (225-275 g) were 35% diet restricted compared to their AL cohorts for 21 days and on day 22 they received a single dose of TA (600 mg/kg, i.p.). Liver injury was assessed by plasma ALT and by histopathological examination of liver sections. Tissue repair was assessed by [3H]thymidine incorporation into hepatonuclear DNA and proliferating cell nuclear antigen (PCNA) immunohistochemistry during 0-120 h after TA injection. In AL-fed rats hepatic necrosis was evident at 12 h, peaked at 60 h, and persisted thereafter until mortality (3 to 6 days). Peak liver injury was approximately twofold higher in DR rats compared to that seen in AL rats. Hepatic necrosis was evident at 36 h, peaked at 48 h, persisted until 96 h, and returned to normal by 120 h. Light microscopy of liver sections revealed progression of hepatic injury in AL rats whereas injury regressed completely leading to recovery of DR rats by 120 h. Progression of injury led to 90% mortality in AL rats vs 30% mortality in DR group. In the surviving AL rats, S-phase DNA synthesis was evident at 60 h, peaked at 72 h, and declined to base level by 120 h, whereas in DR rats S-phase DNA synthesis was evident at 36 h and was consistently higher until 96 h reaching control levels by 120 h. PCNA studies showed a corresponding increase in cells in S and M phase in the AL and DR groups. DR resulted in

Topics: Animals; Carcinogens; Cell Division; Chemical and Drug Induced Liver Injury; Diet; Glycogen; Liver; Liver Diseases; Liver Function Tests; Liver Regeneration; Male; Rats; Rats, Sprague-Dawley; Thioacetamide

Swelling with nonlipid cytoplasmic vacuolation of diffusely distributed hepatocytes is seen consistently after mild acute and subacute liver injury. Several lines of evidence point to the possibility that this change may reflect a cellular adaptation beneficial to the host, rather than a degenerative change. The nature and significance of this morphological manifestation were tested in batches of albino rats given small doses of a variety of hepatotoxins, some of which were subsequently challenged with a large highly necrogenic dose of carbon tetrachloride (CCl4). Morphological and biochemical investigations showed that cytoplasmic vacuolation of liver cells following low doses of toxins was due to excess accumulation of glycogen, predominantly of the monoparticulate form. These cells lacked features of degeneration or regeneration and were much less susceptible to injury by the large dose CCl4, as assessed by structural and serum enzyme analyses. This tolerance to toxic damage seemed to be associated with excess accumulation of intracellular glycogen. We conclude from these and other observations on animal and human livers that many of the vacuolated hepatocytes seen in liver injury are cells adaptively altered to resist further insult rather than cells undergoing hydropic degeneration, as is commonly believed.

Topics: Adaptation, Physiological; Aflatoxin B1; Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Carcinogens; Chemical and Drug Induced Liver Injury; Cytoplasm; Drug Tolerance; Fasting; Formic Acid Esters; Glycogen; Liver; Liver Diseases; Male; Microscopy, Electron; Rats; Rats, Wistar; Vacuoles

The hepatoprotective effect of colchicine in a model of liver intoxication with galactosamine (GalN), 375 mg/kg, i.p., was studied in rats. At 0.5, 1, 3, 6, 18 and 24 h after GalN intoxication the following markers of liver damage were measured: serum activity of alanine aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, hepatic calcium and glycogen contents, liver lipoperoxidation, and liver plasma membrane activity of alkaline phosphatase, gamma-glutamyltranspeptidase and high-affinity Ca2+-ATPase. 24 h after GalN intoxication increases in serum levels of alanine aminotransferase, alkaline phosphatase and gamma-glutamyltranspeptidase were observed along with decreases in plasma membrane activities of alkaline phosphatase, gamma-glutamyltranspeptidase, and high-affinity Ca2+-ATPase. A sharp increase of lipoperoxidative processes measured as malondialdehyde production was also observed. Pretreatment of rats with colchicine 10 micrograms/rat/day p.o. for 7 days before GalN injection prevented partially the toxic effects of GalN. When a dose of 50 micrograms/rat/day for 7 days was given the drug prevented almost completely the damage induced by galactosamine, with the exception of glycogen and serum alkaline phosphatase that remained different from controls. Time-course experiments showed that malondialdehyde formation increased 30 min after intoxication while all other changes became apparent from 6 h after treatment, suggesting that lipoperoxidation may be a prerequisite for galactosamine-induced damage. The protection offered by colchicine was related to its capacity to inhibit lipoperoxidation. Histochemical findings paralleled the biochemical results. The possible role of lipoperoxidation in galactosamine-induced liver damage is discussed.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Calcium; Calcium-Transporting ATPases; Chemical and Drug Induced Liver Injury; Colchicine; Disease Models, Animal; Galactosamine; gamma-Glutamyltransferase; Glycogen; Lipid Peroxidation; Liver; Male; Rats; Rats, Inbred Strains

Previous studies have shown that a chlorinated pesticide, chlordecone (Kepone), greatly potentiates carbon tetrachloride (CCl4) hepatotoxicity and lethality (Curtis, L.R., Williams, W.L., and Mehendale, H.M. (1979). Toxicol. Appl. Pharmacol. 51, 283-293; Curtis, L.R., and Mehendale, H.M. (1980). Drug Metab. Dispos. 8, 23-27). The present study describes sequential morphologic changes which occurred in livers of rats given a "nontoxic" level of chlordecone (10 ppm for 15 days) followed by a single injection of CCl4 (0.1 ml/kg). The hepatic alterations were examined 1 to 36 hr after exposure of the rats to CCl4. Those changes were compared to hepatic alterations which occurred in rats that received the same dose of chlordecone (10 ppm for 15 days) or a single injection of CClr (0.1 ml/kg) alone. The only change noted in livers from rats that received chlordecone alone was focal increase in smooth endoplasmic reticulum (SER) of hepatocytes at 24 hr and continuing throughout the time course of the experiment. Livers from animals that received CCl4 alone showed morphologic changes at 6 hr consisting of glycogen loss, increase in SER, and dilatation of rough endoplasmic reticulum (RER) in pericentral hepatocytes. Accumulation of small lipid droplets was also noted in midzonal hepatocytes. After 6 hr, there was no further increase in severity of injury. At 12 hr recovery was noticeable and, by 36 hr, livers from the CCl4 group appeared normal. Prior administration of chlordecone greatly potentiated pathologic changes in livers of animals that received CCl4. By 4 hr, there was total loss of glycogen in hepatocytes throughout the entire lobule. Small lipid droplets were present in pericentral, midzonal and periportal hepatocytes. Hepatocytes with extremely dilated RER were randomly scattered throughout the entire lobule. At 6 hr, there was further accumulation of lipid in the form of large droplets in hepatocytes. Focal, necrotic cells surrounded by polymorphonuclear leukocytes were randomly distributed throughout the lobule. The number of necrotic foci had progressively increased at the 12- and 24-hr intervals. By 36 hr, confluent areas of necrosis in pericentral and midzonal areas were observed in livers of some animals. This study indicates that although the combination of chlordecone and CCl4 produces much greater hepatic injury resembling damage due to a massive dose of CCl4, histologically, some differences in the progression and distribution of hepatocellul

Topics: Animals; Carbon Tetrachloride; Cell Nucleus; Chemical and Drug Induced Liver Injury; Chlordecone; Cytoplasm; Drug Synergism; Endoplasmic Reticulum; Glycogen; Insecticides; Kinetics; Liver; Liver Diseases; Male; Microscopy, Electron; Rats; Rats, Inbred Strains

The present study, conducted over a time course of 36 hr after CCl4 administration, describes sequential morphometric and biochemical changes which occur in livers of rats exposed to a combination of low levels of chlordecone (10 ppm for 15 days) and a single ip injection of CCl4 (0.1 ml/kg). Those changes were compared to hepatic alterations which occur in rats that received the same dose of chlordecone or CCl4 alone. Biochemical studies showed only trivial increases in levels of glutamic-pyruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT), and moderate but temporary increases in isocitrate dehydrogenase (ICD) after CCl4 alone. The combination of chlordecone and CCl4 resulted in significantly greater elevations of all three serum enzymes at all time intervals examined. Morphometric data showed no difference between normal diet controls and animals exposed to chlordecone alone as far as numerical density of hepatocytes or volume densities of hepatocytes with glycogen, lipid, dilated rough endoplasmic reticulum (RER), pyknosis, or mitoses. Morphometric analysis of livers from animals that received CCl4 alone showed decreases in numerical density, temporary decrease in percentage of hepatocytes containing glycogen, an increase in hepatocytes containing lipid, temporary increase in hepatocytes with dilated RER, and temporary increases in pyknotic nuclei. Soon after the initial hepatic injury was histologically evident between 4 and 6 hr, the number of mitoses increased dramatically and this progressed until complete recovery from CCl4 damage. From all indices of damage, complete recovery was evident by 36 hr after CCl4 administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Cell Nucleus; Chemical and Drug Induced Liver Injury; Chlordecone; Drug Synergism; Endoplasmic Reticulum; Glycogen; Insecticides; Isocitrate Dehydrogenase; Kinetics; Lipid Metabolism; Liver Diseases; Male; Mitosis; Rats; Rats, Inbred Strains

The development of hepatitis, induced in 48 rats by the administration of galactosamine (GalN) in varying doses, was studied with the use of substrate and enzyme histochemical techniques. The so-called atypical glycogen, which is at first highly resistant to diastase, was shown to be digestible after deamination. The increasing accumulation of atypical glycogen during the course of GalN-hepatitis conceals the loss of normal glycogen when the PAS-reaction is used. Nevertheless glycogenolysis could also be demonstrated by the increasing activity of phosphorylase. The acid phosphatase activity was progressively diminished, which was interpreted as signifying early lysosomal damage. G6Pase activity remained nearly constant but SDH showed a decrease in activity after 12 h. These histochemical results are considered to provide deeper insight into the pathological mechanism of GalN-hepatitis.

Topics: Acid Phosphatase; Animals; Carbohydrate Metabolism; Chemical and Drug Induced Liver Injury; Galactosamine; Glucose-6-Phosphatase; Glycogen; Liver; Male; Phosphorylases; Rats; Succinate Dehydrogenase

The effects of hexachlorocyclohexane (HCHCH) on the weight of the liver, content of protein, glycogen, total lipids as well as morphological and ultrastructural changes in the liver were studied. It was established that HCHCH caused a considerable increase in the weight of the liver, as well as in the levels of protein, glycogen and total lipids, which was particularly pronounced following prolonged administration of HCHCH in the dose 1/50 LD50. Large doses of HCHCH (1/3 LD50) brought about marked dystrophic changes in the liver similar to the type of hydropic degeneration, accumulation of fatty drops in hepatocytes Application of a dose 1/50 LD50 of HCHCH resulted in an increased size of hepatocytes, dystrophic changes being noted only in individual cells. Histochemisally there were revealed high levels of RNA and glycogen in hepatocytes. An-Electron-microscopy study of hepatic cells showed the most manifested changes in the endoplasmatic network of hepatocytes, which were seen in an enlargement of the elements of the smooth endoplasmatic reticulum. A suggestion was put forward that the changes indicated above were associated with a stimulating effect of HCHCH on the microsomic system of hepatocytes, i.e. on the enzymatic systems localized in the smooth endoplasmatic network.

Topics: Animals; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Glycogen; Hexachlorocyclohexane; Lipid Metabolism; Liver; Male; Organ Size; Proteins; Rats; RNA

Rats were given a single dose of aflatoxin B1 lethal to 50% of the animals (7.20 mg/kg). Their livers were examined histochemically in correlation with sequential histological lesions. Early periportal liver cell necrosis and marked biliary cell proliferation were observed. Periportal cytoplasmic glycogen and RNA depletion occurred during this early period and subsequently extended to the whole lobule. The enzymes investigated decreased or disappeared in the periportal area; but alkaline phosphatase increased strikingly in the centrolobular area, whereas canalicular adenosinetriphosphatase completely disappeared throughout the liver lobule. The histochemical changes reverted to normal after cessation of the necrosis. Histochemical techniques were more sensitive in detecting the vulnerability of the periportal parenchyma to aflatoxin. After the necrosis, regenerative foci appeared. They showed a variable content in glycogen and RNA and were characteristically enzyme deficient. This reflects the immaturity of regenerating hepatocytes. These early foci subsequently disappeared and are thus considered irrelevant to hepatomagenesis.

Topics: Adenosine Triphosphatases; Aflatoxins; Alkaline Phosphatase; Animals; Bile Ducts, Intrahepatic; Cell Division; Chemical and Drug Induced Liver Injury; Glycogen; Liver; Liver Regeneration; Male; Rats; RNA

Male Wistar rats were given 50 mug of aflatoxin B1 twice a week for 4 weeks, and thereafter 75 mug twice a week for 10 weeks. Their livers were investigated histologically and histochemically for glycogen, RNA, fat, alkaline and acid phosphatases, adenosine triphosphatase, 5'-nucleotidase, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, succinic dehydrogenase, and alkaline and acid nucleases. No significant lesions occurred before 15 weeks. During this period, the liver was histochemically unchanged except for a periportal decrease of alkaline phosphatase and adenosine triphosphatase. Scattered hepatocytes with a strong glucose-6-phosphatase activity appeared. These changes represent toxic effects of aflatoxin B1 and are irrelevant to carcinogenesis. From 15 weeks onward, three types of liver cell hyperplastic foci and nodules developed. Histologically, and with respect to glycogen, fat, and RNA content, only two of these types were considered as potential precursors of hepatocarcinomas. However, all types exhibited a decrease or absence of the enzymes studied. Both histological and histochemical changes stressed the complex heterogeneity existing between and within hepatic foci and nodules. From 11 months on, hepatocarcinomas developed. The tumors disclosed similar histochemical changes. This similarity further supports the "precarcinomatous" nature of hyperplastic foci and nodules. It appears that focal changes in surface as well as in cytoplasmic and nuclear enzymes are intimately and very early linked to the carcinogenic process. Whether they are fundamental or only represent an epiphenomenon remains unclear.

Topics: Acid Phosphatase; Adenosine Triphosphatases; Aflatoxins; Alkaline Phosphatase; Animals; Chemical and Drug Induced Liver Injury; Glucose-6-Phosphatase; Glucosephosphate Dehydrogenase; Glycogen; Lipid Metabolism; Liver Neoplasms; Male; Neoplasms, Experimental; Nucleotidases; Precancerous Conditions; Rats; RNA, Neoplasm; Succinate Dehydrogenase; Time Factors

The hepatic lesion in Reye's syndrome (acute encephalopathy with fatty degeneration of viscera) was studied by light microscopy of sequential biopsy specimens obtained in 49 children. The hepatic lesion is a morphologically characteristic, rapidly evolving, and reversible toxic hepatitis. In specimens obtained with 48 hr of onset of neurological deterioration, the severity of the diffuse microvesicular steatosis is best appreciated in frozen sections stained for lipid content. Variation in severity of hepatocyte glycogen depletion in early biopsies correlates with other histological measures of severity, and with the occurrence of hypoglycemia, severity of the encephalopathy at the time of admission, and mortality rate. Histochemical studies suggest that the hepatic lesion is attributable to mitochondrial injury and other evidence that supports this hypothesis is briefly reviewed. The etiology of the syndrome and its relationship to the viral disease which usually precedes it are unknown.

Topics: Brain Diseases; Chemical and Drug Induced Liver Injury; Fatty Liver; Glycogen; Humans; Lipid Metabolism; Liver; Mitochondria, Liver; Reye Syndrome

Topics: Animals; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum; Glycogen; Hyperplasia; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Microscopy, Electron; Rats; Ribosomes; Thioacetamide; Time Factors; Water

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cytoplasm; Endoplasmic Reticulum; Glycogen; Golgi Apparatus; Lipids; Liver; Liver Regeneration; Lysosomes; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mitochondria

Topics: Acid Phosphatase; Animals; Chemical and Drug Induced Liver Injury; Esterases; Female; Glycogen; Histocytochemistry; L-Lactate Dehydrogenase; Lanthanum; Liver; Liver Diseases; Malate Dehydrogenase; Male; Phosphorylase Kinase; Rats; Succinate Dehydrogenase

Topics: Adenosine Triphosphate; Animals; Chemical and Drug Induced Liver Injury; Cytoplasm; Drug Synergism; Edema; Endoplasmic Reticulum; Fructose; Fructose-Bisphosphate Aldolase; Glucose; Glycogen; Golgi Apparatus; Infusions, Parenteral; Inosine Nucleotides; Liver; Male; Microscopy, Electron; Rats; Water

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Child, Preschool; Endoplasmic Reticulum; Glycogen; Humans; Isoniazid; Liver; Lysosomes; Male; Microscopy, Electron; Mitochondria, Liver; Phenylketonurias

Topics: Adenosine Triphosphatases; Alkaline Phosphatase; Animals; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cold Temperature; Drug Tolerance; Glutamate Dehydrogenase; Glycogen; Histocytochemistry; Lipid Metabolism; Liver; Liver Diseases; Mice; Necrosis; Staining and Labeling; Time Factors

Topics: Animal Feed; Animals; Chemical and Drug Induced Liver Injury; Cytoplasm; Diet; Endoplasmic Reticulum; Fossil Fuels; Glycogen; Hydrazines; Inclusion Bodies; Liver; Microscopy, Electron; Mitochondria, Liver; Turkeys

Topics: Animals; Biopsy; Carbohydrate Metabolism, Inborn Errors; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Endoplasmic Reticulum; Fructose; Galactose; Glucose; Glycogen; Golgi Apparatus; Humans; Liver; Liver Diseases; Male; Mannitol; Mannose; Microscopy; Microscopy, Electron; Rats; Rats, Inbred Strains; Ribosomes

Topics: Administration, Oral; Adrenal Cortex Hormones; Aminoglutethimide; Animals; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum; Female; Glycogen; Hyperplasia; Liver; Male; Microscopy, Electron; Microsomes, Liver; Rats

Topics: Aging; Alanine Transaminase; Amino Acids; Animals; Aspartate Aminotransferases; Blood Glucose; Carbon Tetrachloride Poisoning; Catalase; Chemical and Drug Induced Liver Injury; Glycogen; Mice; Rabbits; Rats; Trace Elements; Vitamins; Water-Electrolyte Balance

Topics: Alcoholic Intoxication; Alcohols; Animals; Chemical and Drug Induced Liver Injury; Flavonoids; Glycogen; Humans; Liver; Male; Microscopy, Electron; Mitochondria; Rats

Topics: Adenosine Triphosphatases; Alcohol Oxidoreductases; Alkaline Phosphatase; Animals; Arginase; Aspartate Aminotransferases; Basophils; Bile Ducts, Intrahepatic; Chemical and Drug Induced Liver Injury; Connective Tissue; Cytoplasm; Esterases; Glutamate Dehydrogenase; Glutamates; Glycogen; Halothane; Horse Diseases; Horses; Liver; Necrosis; Staining and Labeling; Succinate Dehydrogenase

Topics: Alcohols; Animals; Carbohydrate Metabolism; Carbon Isotopes; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Experimental; Glucose; Glycogen; In Vitro Techniques; Injections, Subcutaneous; Liver; Male; Rats; Time Factors; Xylitol

Topics: Aflatoxins; Animals; Body Weight; Chemical and Drug Induced Liver Injury; Glycogen; Liver Diseases; Male; Necrosis; Rabbits; Skin Absorption; Time Factors

Topics: Animals; Aspartate Aminotransferases; Cattle; Chemical and Drug Induced Liver Injury; Chloroform; Ethyl Ethers; Gluconeogenesis; Glycogen; Halothane; In Vitro Techniques; Lactates; Liver; Oxygen Consumption; Perfusion

Topics: Animals; Cattle; Chemical and Drug Induced Liver Injury; Female; Galactose; Glucuronates; Glycogen; Hexosamines; Hexosephosphates; Kinetics; Liver; Nucleotidyltransferases; Polysaccharides; Rats; Uracil Nucleotides

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Chronic Disease; Cytoplasmic Granules; Endoplasmic Reticulum; Glycogen; Hemochromatosis; Humans; Hypertrophy; Liver; Liver Cirrhosis; Liver Neoplasms; Microscopy, Electron

Topics: Alkaline Phosphatase; Animals; Antitoxins; Chemical and Drug Induced Liver Injury; Corynebacterium; Corynebacterium pyogenes; Exotoxins; Female; Glycogen; Goats; Hepatitis; Histocytochemistry; Humans; Liver; Liver Glycogen; Mammary Glands, Animal; Mastitis; Research; Toxins, Biological

Topics: Alkaloids; Animals; Chemical and Drug Induced Liver Injury; Glycogen; Growth Hormone; Hepatitis; Lipid Metabolism; Liver; Liver Cirrhosis; Liver Cirrhosis, Experimental; Liver Glycogen; Pharmacology; Rats; Research

Topics: Acid Phosphatase; Alkaline Phosphatase; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Electron Transport Complex II; Glycogen; Hepatitis A; Histocytochemistry; Metabolism; Pathology; Rabbits; Research; Skin; Succinate Dehydrogenase; Toxicology

Topics: Alkaline Phosphatase; Animals; Bile; Carbohydrate Metabolism; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Dogs; Glycogen; Hepatitis; Hormones; Lipid Metabolism; Liver; Pharmacology; Pineal Gland; Rats

Topics: Chemical and Drug Induced Liver Injury; Glycogen; Lipids; Liver; Methionine; Monosaccharides; Pharmaceutical Preparations; Proteins