amanitins and Chemical-and-Drug-Induced-Liver-Injury

More than 90% of all fatal mushroom poisonings worldwide are due to amatoxin containing species that grow abundantly in Europe, South Asia, and the Indian subcontinent. Many cases have also been reported in North America. Initial symptoms of abdominal cramps, vomiting, and a severe cholera-like diarrhea generally do not manifest until at least six to eight hours following ingestion and can be followed by renal and hepatic failure. Outcomes range from complete recovery to fulminant organ failure and death which can sometimes be averted by liver transplant. There are no controlled clinical studies available due to ethical reasons, but uncontrolled trials and case reports describe successful treatment with intravenous silibinin (Legalon® SIL). In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10% in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin. Silibinin, a proven antioxidative and anti-inflammatory acting flavonolignan isolated from milk thistle extracts, has been shown to interact with specific hepatic transport proteins blocking cellular amatoxin re-uptake and thus interrupting enterohepatic circulation of the toxin. The addition of intravenous silibinin to aggressive intravenous fluid management serves to arrest and allow reversal of the manifestation of fulminant hepatic failure, even in severely poisoned patients. These findings together with the available clinical experience justify the use of silibinin as Legalon® SIL in Amanita poisoning cases.

Topics: Amanitins; Animals; Antidotes; Chemical and Drug Induced Liver Injury; Humans; Molecular Structure; Mushroom Poisoning; Silymarin; Tissue Distribution; Treatment Outcome

Silibinin is the most active component of a complex of flavonoids -silymarin contained in fruit milk thistle (Sylibum marianum). Its mechanism of action is complex and highly beneficial in protecting hepatocytes. On the one hand this compound blocks the penetration of various toxins (for example amanitin) into the hepatocytes not allowing in this way for the cell death and on the other hand, it prevents apoptosis through intracellular. It protects the liver from oxidative intracellular free radicals by increasing the activity of enzyme superoxide dismutase and peroxidase, as well as by increasing the concentration of glutathione and the activity of the peroxidase. Silibinin strengthens and stabilizes the cell membranes, inhibits the synthesis of prostaglandins associated with the lipid peroxidation and promotes regeneration of liver through the stimulation of protein synthesis and effect on the production of new hepatocytes. A particularly interesting topic from the perspective of a toxicologist is the application of silibinin in Amanita phalloides poisoning. Clinical trials conducted in this respect are very encouraging. The other beneficial application of silibinin is in therapy of the alcoholic liver cirrhosis. The evidence shows that the use of silymarin leads to a significant reduction in liver-related mortality and even reduction in the number of patients with encephalopathy in the course of the disease. Application of silibinin goes beyond liver disease and expands in the direction of cancer and even diabetes. What is interesting is the fact, that the substance of herbal origin occurring in the environment is so strong, favorable, beneficial and multidirectional. Science has contributed to improving the bioavailability of silibinin thus making it more effective.

Topics: Amanita; Amanitins; Chemical and Drug Induced Liver Injury; Hepatocytes; Humans; Lipid Peroxidation; Liver Diseases; Liver Regeneration; Mushroom Poisoning; Peroxidases; Prostaglandins; Protective Agents; Silybin; Silymarin; Superoxide Dismutase

Amatoxin poisoning is a medical emergency characterized by a long incubation time lag, gastrointestinal and hepatotoxic phases, coma, and death. This mushroom intoxication is ascribed to 35 amatoxin-containing species belonging to three genera: Amanita, Galerina, and Lepiota. The major amatoxins, the alpha-, beta-, and gamma-amanitins, are bicyclic octapeptide derivatives that damage the liver and kidney via irreversible binding to RNA polymerase II.. The mycology and clinical syndrome of amatoxin poisoning are reviewed. Clinical data from 2108 hospitalized amatoxin poisoning exposures as reported in the medical literature from North America and Europe over the last 20 years were compiled. Preliminary medical care, supportive measures, specific treatments used singly or in combination, and liver transplantation were characterized. Specific treatments consisted of detoxication procedures (e.g., toxin removal from bile and urine, and extracorporeal purification) and administration of drugs. Chemotherapy included benzylpenicillin or other beta-lactam antibiotics, silymarin complex, thioctic acid, antioxidant drugs, hormones and steroids administered singly, or more usually, in combination. Supportive measures alone and 10 specific treatment regimens were analyzed relative to mortality.. Benzylpenicillin (Penicillin G) alone and in association was the mostfrequently utilized chemotherapy but showed little efficacy. No benefit was found for the use of thioctic acid or steroids. Chi-square statistical comparison of survivors and dead vs. treated individuals supported silybin, administered either as mono-chemotherapy or in drug combination and N-acetylcysteine as mono-chemotherapy as the most effective therapeutic modes. Future clinical research should focus on confirming the efficacy of silybin, N-acetylcysteine, and detoxication procedures.

Topics: Agaricales; Amanitins; Animals; Chemical and Drug Induced Liver Injury; Emergency Medical Services; Humans; Liver Transplantation; Mushroom Poisoning; Retrospective Studies

Poisoning with mushrooms of the genus Amanita, members of which occur frequently in both North America and Europe, accounts for a significant number of deaths annually. Liver damage is the main clinical feature and death rates are variously reported to be from 11.3% to 51.3% of patients. The amount of mushroom ingested appears to be the main prognostic indicator and a fatal outcome appears inevitable if a large amount is eaten. In sublethal exposures, supportive therapy seems effective; when definitive treatment is considered, hyperbaric oxygen, penicillin and silymarin are indicated in conjunction with careful management of blood glucose concentration. Charcoal hemoperfusion, forced diuresis, hyperbaric oxygen, and thioctic acid may also be considered, although these treatment modalities are not clearly associated with increased survival.

Topics: Amanitins; Animals; Blood Glucose; Charcoal; Chemical and Drug Induced Liver Injury; Diuresis; Glucose; Hemoperfusion; Humans; Mushroom Poisoning; Silymarin; Thioctic Acid

Topics: Acetaminophen; Amanitins; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Humans; Phalloidine; Tetracyclines

Mushroom toxicity is the main branch of foodborne poisoning, and liver damage caused by amatoxin poisoning accounts for more than 90 % of deaths due to mushroom poisoning. Alpha-amatoxin (α-AMA) has been considered the primary toxin from amatoxin-containing mushrooms, which is responsible for hepatotoxicity and death. However, the mechanism underlying liver failure due to α-AMA remains unclear. This study constructed animal and cell models. In the animal experiments, we investigated liver injury in BALB/c mice at different time points after α-AMA treatment, and explored the process of inflammatory infiltration using immunohistochemistry and western blotting. Then, a metabonomics method based on gas chromatography mass spectrometry (GCMS) was established to study the effect of α-AMA on liver metabonomics. The results showed a significant difference in liver metabolism between the exposed and control mice groups that coincided with pathological and biochemical indicators. Moreover, 20 metabolites and 4 metabolic pathways related to its mechanism of action were identified, which suggested that energy disorders related to mitochondrial dysfunction may be one of the causes of death. The significant changes of trehalose and the fluctuation of LC3-II and sqstm1 p62 protein levels indicated that autophagy was also involved in the damage process, suggesting that autophagy may participate in the clearance process of damaged mitochondria after poisoning. Then, we constructed an α-AMA-induced human normal liver cells (L-02 cells) injury model. The above hypothesis was further verified by detecting cell necrosis, mitochondrial reactive oxygen species (mtROS), mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (Δψ m), and cellular ATP level. Collectively, our results serve as direct evidence of elevated in vivo hepatic mitochondrial metabolism in α-AMA-exposed mice and suggest that mitochondrial dysfunction plays an important role in the early stage of α-AMA induced liver failure.

Topics: Amanitins; Animals; Cell Line; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Energy Metabolism; Humans; Liver; Liver Failure; Metabolomics; Mice, Inbred BALB C; Mitochondria, Liver; Mushroom Poisoning; Time Factors

The amanitins (namely α- and β-amanitin) contained in certain mushrooms are bicyclic octapeptides that, when ingested, are responsible for potentially lethal hepatotoxicity. M101 is an extracellular hemoglobin extracted from the marine worm Arenicola marina. It has intrinsic Cu/Zn-SOD-like activity and is currently used as an oxygen carrier in organ preservation solutions. Our present results suggest that M101 might be effective in reducing amanitin-induced hepatotoxicity and may have potential for therapeutic development.

Topics: Amanitins; Chemical and Drug Induced Liver Injury; Hemoglobins; Humans; Oxygen

Published estimates of survival associated with mushroom (amatoxin)-induced acute liver failure (ALF) and injury (ALI) with and without liver transplant (LT) are highly variable. We aimed to determine the 21-day survival associated with amatoxin-induced ALI (A-ALI) and ALF (A-ALF) and review use of targeted therapies.. Cohort study of all A-ALI/A-ALF patients enrolled in the US ALFSG registry between 01/1998 and 12/2014.. Of the 2224 subjects in the registry, 18 (0.8%) had A-ALF (n = 13) or A-ALI (n = 5). At admission, ALF patients had higher lactate levels (5.2 vs. 2.2 mm, P = 0.06) compared to ALI patients, but INR (2.8 vs. 2.2), bilirubin (87 vs. 26 μm) and MELD scores (28 vs. 24) were similar (P > 0.2 for all). Of the 13 patients with ALF, six survived without LT (46%), five survived with LT (39%) and two died without LT (15%). Of the five patients with ALI, four (80%) recovered and one (20%) survived post-LT. Comparing those who died/received LT (non-spontaneous survivors [NSS]) with spontaneous survivors (SS), N-acetylcysteine was used in nearly all patients (NSS 88% vs. SS 80%); whereas, silibinin (25% vs. 50%), penicillin (50% vs. 25%) and nasobiliary drainage (0 vs. 10%) were used less frequently (P > 0.15 for all therapies).. Patients with mushroom poisoning with ALI have favourable survival, while around half of those presenting with ALF may eventually require LT. Further study is needed to define optimal management (including the use of targeted therapies) to improve survival, particularly in the absence of LT.

Topics: Acetylcysteine; Adult; Amanitins; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Humans; Liver Failure, Acute; Liver Transplantation; Male; Middle Aged; Mushroom Poisoning; North America; Penicillins; Registries; Silybin; Silymarin

Topics: Alpha-Amanitin; Amanitins; Animals; Antidotes; Chemical and Drug Induced Liver Injury; Cimetidine; Humans; Mice; Mushroom Poisoning

The foraging of wild mushrooms can be complicated by toxicity from several mushroom types. Amatoxin, a peptide contained in several mushroom species, accounts for the majority of severe mushroom poisonings by binding to RNA polymerase II irreversibly, leading to severe hepatonecrosis. There is no effective antidote for severe amatoxin poisoning. We compare the effectiveness of 5 potential antidotal therapies in limiting the degree of hepatonecrosis in a randomized, controlled, murine model of amatoxin-induced hepatotoxicity.. One hundred eighty male Institute of Cancer Research mice were randomized into 6 equal groups. Within each group, 21 mice were intraperitoneally injected with 0.6 mg/kg of alpha-amanitin (amatoxin); the remaining 9 were injected with 0.9% normal saline solution. Four hours postinjection, each group of 30 mice was randomized to 1 of 5 intraperitoneal treatments (N-acetylcysteine, benzylpenicillin, cimetidine, thioctic acid, or silybin) or normal saline solution. Repeated dosing was administered intraperitoneally every 4 to 6 hours for 48 hours. After 48 hours of treatment, each subject was killed, cardiac blood was aspirated for hepatic aminotransferase measurements (alanine transaminase and aspartate transaminase), and liver specimens were harvested to evaluate the extent of hepatonecrosis. The degree of hepatonecrosis was determined by a pathologist blinded to the treatment group and divided into 5 categories according to percentage of hepatonecrosis.. Amanitin significantly increased aspartate transaminase in treated mice compared with normal saline solution-treated controls (mean [SD] 2,441 [2,818] IU/L versus 310 [252]; P=.03). None of the antidotal therapies were found to significantly decrease the increase in aminotransferases compared with controls. Further, none of the antidotal therapies demonstrated an important decrease in hepatonecrosis compared with controls when a histologic grading scale was used.. In this murine model, N-acetylcysteine, benzylpenicillin, cimetidine, thioctic acid, and silybin were not effective in limiting hepatic injury after alpha-amanitin poisoning. Increases of aminotransferases and degrees of histologic hepatonecrosis were not attenuated by these antidotal therapies.

Topics: Acetylcysteine; Alanine Transaminase; Amanitins; Animals; Antidotes; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cimetidine; Disease Models, Animal; Male; Mice; Mushroom Poisoning; Penicillin G; Random Allocation; Silybin; Silymarin; Thioctic Acid

Mortality from ingestions of the mushroom Amanita phalloides remains as high as 20-40% with many surviving patients requiring liver transplantation. A variety of treatments for Amanita ingestion have been evaluated, yet other than supportive measures, no effective therapy has been identified. In addition, an antidote for Amanita toxicity may not be practical due to delayed patient presentation. The drug amifostine was proposed to potentially improve survival from alpha-amanitin toxicity by conferring cytoprotective effects on hepatocytes at risk for cell death. Amifostine is used as a radio--and chemo-protective agent. It protects against lipoperoxidation, interferes with the cross-linking of DNA, and may act by other mechanisms yet to be identified, making it attractive for potentially attenuating ongoing hepatic necrosis. It has not previously been studied in a toxicologic model.. To determine whether amifostine is an effective postexposure therapy for alpha-amanitin, the primary lethal toxin in Amanita phalloides.. Swiss mice (n = 30 in all groups) were given an approximate LD75 dose of intraperitoneal (i.p.) alpha-amanitin. Amifostine was administered i.p. 6 h after poisoning in three cumulative dosing groups: 250 mg/kg; 500 mg/kg; and 1600 mg/kg. Controls received equal volumes of i.p. sterile 0.9% saline. Mice were monitored and time of death recorded. At day 7, survival was assumed and the remaining mice were euthanized. Qualitative histologic comparisons of hepatic and renal toxicity were performed.. At day 7, only 10% of the control mice survived. Survival in the amifostine 250, 500, and 1600 mg/kg groups was 20%, 20%, and 3%, respectively. No statistically significant differences were detected in Kaplan-Meier survival between the control group and those receiving 250 or 500 mg/kg; however, there was a statistically significant decrease in survival for the group receiving 1600 mg/kg (p = 0.0002).. No survival benefit was seen with cumulative doses between 250 and 500 mg/kg; however, higher doses may result in subsequent toxicity and decreased survival.

Topics: Amanitins; Amifostine; Animals; Cell Death; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Free Radical Scavengers; Hepatocytes; Kidney; Lethal Dose 50; Liver; Mice; Nucleic Acid Synthesis Inhibitors; Survival Analysis

Acute phase responses to intragastric administration of a single dose of CCl(4) were examined with albumin mRNA turnover as a marker. Based on the combination of the changes in stability of albumin mRNA and activity of transcription of its gene, the entire course of liver injury was classified into three stages, the first stage for aggravation of injury until 9 h, the second from 9 to 24 h, and the third for repair of injury or regeneration of liver after 48 h. Liver S100 fractions from normal and CCl(4)-treated rats contained, in total, 11 polypeptides cross-linked with part of albumin mRNA, although they did not appear to be specific to this mRNA. Their profiles were altered together with the changes in stability of albumin mRNA in different stages. These findings suggest that the polypeptides with distinct properties play roles in physiologically significant processes involved in utilization and turnover of albumin mRNA, apparently altering its stability.

Topics: Acute-Phase Reaction; Albumins; Amanitins; Animals; Base Sequence; Binding, Competitive; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Gene Expression Regulation; Half-Life; Liver; Liver Diseases; Male; Molecular Weight; Peptides; Protein Binding; Rats; Rats, Wistar; RNA Probes; RNA Stability; RNA-Binding Proteins; RNA, Messenger; Substrate Specificity; Time Factors; Transcription, Genetic

We report here three cases of Amanita virosa induced toxic hepatitis. Two of the three cases recovered but the other died 10 days after mushroom ingestion. Since the mortality of Amanita mushroom induced toxic hepatitis is very high, prompt diagnosis and aggressive therapeutic measures should be initiated as soon as possible. Our cases showed that the initial serum aminotransferase levels might not predict the clinical outcome of the patient, but that the prothrombin time (PT) seemed to be a more useful prognostic marker. Close monitoring of aminotransferase levels and PT as well as appropriate therapy are recommended. All three cases showed signs of proteinuria and we were able to characterize mixed tubular and glomerular type proteinuria at 3 or 4 days after ingestion in two cases. Among the previously reported Korean cases of suspected Amanita induced toxic hepatitis, most species could not be identified except for four cases of Amanita virosa. No cases of Amanita phalloides induced toxic hepatitis have been identified in Korea so far.

Topics: Adult; Amanita; Amanitins; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Middle Aged; Mushroom Poisoning; Proteinuria

Mushrooms of the genus Lepiota (helveola and bruneo-incarnata), similar to those of the genus Amanita, contain amatoxins. Amatoxins, especially amanitin, cause cellular destruction by inhibiting RNA polymerase. Due to the hepatic toxicity of these mushrooms, we have assessed their incidence on alkaline phosphatase levels and on its isoenzymes. Total alkaline phosphatase activity levels were not found to be increased except in two patients, and then only moderately. As regards isoenzymes, the occurrence of a double hepatic fraction in five of the 10 patients, is the most remarkable finding. There seems to exist a relatively close correspondence between the occurrence of a hepatic2 fraction correlating with those of urine amanitin. We conclude that the hepatic2 fraction proves to be important in assessing liver damage by mushroom poisoning because of its correlation with the patient's degree of poisoning.

Topics: Alanine Transaminase; Alkaline Phosphatase; Amanitins; Chemical and Drug Induced Liver Injury; Electrophoresis; Humans; Isoenzymes; Mushroom Poisoning; Prognosis; Regression Analysis

Forty-eight hours after a women was poisoned by ingesting Amanita phalloides mushrooms, she developed fulminant hepatic failure with collapse, pH 7.24, lactic acidosis 7.6 mmol/l, hypoglycaemia 3.5 mmol/l, anuria and stage IV coma requiring tracheal intubation and mechanical ventilation. Transaminase level was up to 8,000 UI/l. Prothrombin and factor V levels were below 10 percent, with an APT time of 86 s versus a 29 s control time. Twenty-four hours after her admission, the patient underwent orthotopic liver transplantation. The postoperative period was uneventful, with return to consciousness and rapid normalization of hepatic biochemistry values, without signs of acute rejection. This 10th published case of orthotopic liver transplantation for Amanita phalloides poisoning with acute hepatic necrosis confirms that this type of treatment must be systematically envisaged in all such cases.

Topics: Amanita; Amanitins; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Transplantation; Middle Aged; Mushroom Poisoning; Phalloidine

Twenty-seven consecutive mushroom poisoning cases were followed up over a period of 14 days. Fourteen out of 27 died of liver failure. There were no deaths from renal failure. The mushrooms were identified as the amatoxin-containing Lepiota species. Therapeutic measures included nasogastric lavage, charcoal, vitamin C, vitamin B, penicillin G, corticosteroids, oral streptomycin and, in the case of a few patients, limited amounts of thioctic acid. Of the ten haemodialysed, nine died. Unfortunately charcoal haemoperfusion was not available. It appeared that therapeutic measures were ineffective and it also seemed that the amount of mushroom ingested was the determining factor for the prognosis. An important point to make is that renal failure does not occur and liver failure is always delayed (group II). For this reason all suspected cases of mushroom poisoning, regardless of absence of clinical signs and symptoms, must be hospitalised for a period of at least one week. The poisonous properties of wild mushrooms have been recognized since ancient times. However, despite awareness of their inherent dangers, serious poisoning continues to occur. Fatal intoxications can be attributed almost entirely to the amtoxin-containing species. Amanita phalloides have been blamed for over 90% of poisoning deaths in North America. There are reports of intoxications of other amatoxin-containing species in Europe, but fatalities due to Lepiota species are reported only rarely. It was previously acknowledged that the interval between ingestion of mushrooms and the onset of symptoms is longer than expected in serious poisonings.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Amanitins; Chemical and Drug Induced Liver Injury; Child; Coma; Female; Humans; Male; Middle Aged; Mushroom Poisoning; Prognosis; Renal Dialysis; Thioctic Acid; Time Factors

Topics: Amanitins; Animals; Chemical and Drug Induced Liver Injury; Flavonoids; Injections, Intraperitoneal; Liver Diseases; Male; Mice; Silymarin

Topics: Amanita; Amanitins; Chemical and Drug Induced Liver Injury; Female; Humans; Kidney Diseases; Middle Aged; Mushroom Poisoning

Topics: Aflatoxins; Amanitins; Chemical and Drug Induced Liver Injury; Humans; Hydrocarbons, Halogenated; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Diseases, Alcoholic; Porphyrins

The aim of the present study is to investigate the capacity of damaged rat liver cells to respond to a second inflammation by a change in plasma protein profile, while the first inflammatory process is in progress. Quantitation of these effects would be useful, especially in situations where patients are suffering from complications due to emergence of a new pathological factor. We therefore studied the effect of phalloidin on rat livers already made necrotic by oral intubation of CCl4. Our data showed that a decrease in acute-phase response does not necessarily always imply healing, but may also be indicative of a second pathological complication.

Topics: Amanitins; Animals; Blood Proteins; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; DNA; Immunoelectrophoresis; Liver; Phalloidine; Rats; Rats, Inbred Strains; Thymidine; Time Factors

Rubescenslysin, a haemolytic protein from Amanita rubescens, disrupted the cytoplasmic membrane of human leucocytes which were more sensitive than erythrocytes. In the isolated hearts of rats and guinea pigs it caused systolic contracture, which was preceded by potassium outflow and sometimes by a transient positive inotropic effect. On the electrically stimulated guinea-pig left atrium it showed at first a positive, followed by a negative inotropic effect; on the spontaneously beating right atrium it produced transient positive followed by negative inotropic and chronotropic effects. Atria were less sensitive than intact hearts. In the isolated rat phrenic nerve-diaphragm preparation it produced a contracture, which was associated with reduction of indirect and direct contractility. In the isolated guinea-pig ileum it produced a slow contraction followed by tachyphylaxis. As excitability declined due to rubescenslysin, so did excitability by acetylcholine and potassium. Atropine and pheniramine had only feeble antagonistic effects, but papaverine was more powerful. In isolated rat hepatocytes, rubescenslysin caused a rapid outflow of potassium and coarse cell protrusions while later the cells became stainable with trypan blue. In the isolated perfused rat liver it produced a rapid outflow of potassium and of cytoplasmic and mitochondrial enzymes, and a somewhat slower outflow of lysosomal beta-glucuronidase, accompanied by a rise in the lactate/pyruvate ratio and a decrease in bile production. In the isolated perfused rat kidney it caused an outflow of cytoplasmic and mitochondrial enzymes, together with massive proteinuria and serious restriction of sodium and potassium reabsorption and of urine output. In all the tissues investigated the effects of rubescenslysin began within a few min, were dose-dependent and practically irreversible. There were only minor differences in sensitivity between various organs and species. The observations indicate that the toxin is relatively nonspecific in its attack on components of cell membranes.

Topics: Amanitins; Animals; Cell Membrane; Chemical and Drug Induced Liver Injury; Female; Fungal Proteins; Guinea Pigs; Humans; In Vitro Techniques; Male; Muscle Contraction; Myocardial Contraction; Rats; Rats, Inbred Strains

The stages of vacuolar formations in liver parenchymal cells of rats and mice following application of phalloidine, amanitine, o-phenylphenol, hexachlorophene and p-chloro-m-cresol were demonstrated by electron microscopic investigations. After treatment the intercellular spaces are markedly widened and in restricted regions exhibit large sacculi penetrating into the cytoplasm of adjacent hepatocytes. In cross-sections these invaginations frequently appear as intracellular vacuoles. Our present investigations, however, clearly demonstrate that these vacuoles are still in direct connection with the intercellular space. The vacuolar formation is more pronounced in older animals and it is suggested that an increased patho-physiological portal hypertension leads to the swelling of the intercellular space.

Topics: Aging; Amanitins; Animals; Biphenyl Compounds; Chemical and Drug Induced Liver Injury; Female; Hexachlorophene; Liver; Male; Mice; Organoids; Phalloidine; Rats; Vacuoles

Two proteins with high affinity for amatoxins have been characterized in calf thymus nuclei, the RNA-polymerase II (or B) and a 100 K protein of unknown function. Most of the toxic effects of amatoxins are based on the inhibited synthesis of mRNA. The 100 K protein may be involved in functions of cytokinesis as suggested by experiments with PtK1 cells and a fluorescent labelled amatoxin. The molecular toxicity of phallotoxins can be understood in terms of their affinity for actin. By interaction with rabbit muscle actin the concentration of actin monomers is decreased. In hepatocytes, the phallotoxins change the structure of the microfilamentous web.

Topics: Actins; Amanitins; Animals; Cell Membrane; Chemical and Drug Induced Liver Injury; Liver; Mycotoxins; Protein Binding; Proteins; Rats; RNA Polymerase II; Subcellular Fractions

An analysis of 28 cases of amanita phalloides poisoning serves as basis for a discussion of the clinical features and therapeutic problems involved. A critical review of recent experimental investigations in animals points to new possibilities in the treatment of amanita phalloides poisoning.

Topics: Adult; Amanita; Amanitins; Austria; Chemical and Drug Induced Liver Injury; Child; Exchange Transfusion, Whole Blood; Female; Humans; Male; Mushroom Poisoning; Phalloidine; Prothrombin; Renal Dialysis; Vitamin K

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

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

Comparing the morphological effects of actinomycin D and alpha amanitine on the rat liver, it can be seen that the nuclear alterations caused by actinomycin (=segregation of the nucleolus and condensation of all the chromatin) occur simultaneously. After treatment with amanitine, the lesions appear in two steps. First of all one sees condensation of only the extranucleolar chromatin and fragmentation of the nucleolus. These two phenomena are related to each other not only chronogically but also causetively. In our opinion the shrinkage of the extranucleolar parts of chromosones results in the individual nucleolus-organizers being removed into different quarters of the nucleoplasm. The fragments themselves must not be altered structurally and functionally, as Kedinger and Simard (1974) have already shown. We always observed changes of the nucleolar fragments 30-90 min after the fragmentation. These changes consisted of the condensation of the intranucleolar chromatin, and the segregation and degranulation of the nucleolus, in the same manner found directly after the actinomycin-poisoning in the whole nucleolus. The delay of the lesions observed on the dispersed nucleolar fragments indicates that is a consequence of the amanitine-poisoning -- probably the result of the disturbed protein synthesis and the inactivation of a hypothetical extranucleolar regulatorgene, which controls nucleolar function.

Topics: Amanitins; Animals; Cell Nucleolus; Cell Nucleus; Chemical and Drug Induced Liver Injury; Chromatin; Dactinomycin; Liver; Male; Microscopy, Electron; Nucleoproteins; Rats; RNA; Time Factors

Ethyl (Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)- acetate (piprozoline, Gö 919, Problin) is a new potent choleretic which can be classified as a true cholepoietic agent. Accordingly the substance increases bile fluid and solid content as well. A dose-dependent choleretic effect could be shown in all species investigated. The choleretic effect of piprozoline is long-lasting and superior to that of the other choleretics compared with. There was a significant inhibition of experimentally induced liver damage in animals by piprozoline given prophylactically. Our experiments did not reveal any pharmacological properties interfering with the use of piprozoline as a choleretic.

Topics: Amanitins; Animals; Bile; Bile Acids and Salts; Carbon Tetrachloride Poisoning; Cats; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Dogs; Female; Galactosamine; Lethal Dose 50; Male; Mice; Piperidines; Rats; Thiazoles

Topics: Amanitins; Animals; Cell Nucleus; Chemical and Drug Induced Liver Injury; Drug Synergism; Liver; Male; Mice; Proteins; Serum Albumin

Topics: Adult; Agaricales; Aged; Amanita; Amanitins; Chemical and Drug Induced Liver Injury; Female; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Mushroom Poisoning; Oligopeptides; Phalloidine

The effects of silymarin on the total dry mass and class pattern of rat hepatocytes have been studied during acute poisoning by phalloidin and alpha-amanitine. Phalloidin (2/5 of the LD50) after 3 h causes a marked change in the hepatocyte class pattern due to a displacement of a high percentage of cells in the intervals among classes, while the cell dry mass increases slightly. alpha-Amanitine (1/4 or 1/2 of the LD50) after 3 h causes a decrease in the number of classes of hepatocytes due to a disappearance of the heavier ones, a displacement of cells in the intervals among classes, an appearance of very light cells, and a decrease by about 25% in the mean dry mass of the hepatocytes. Silymarin, administered 30 min before poisoning, prevents all the changes due to 2/5 of the LD50 of phalloidin and to 1/4 of the LD50 of alpha-amanitine, and strongly reduces the effects of 1/2 of the LD50 of alpha-amanitine. The effects of alpha-amanitine and phalloidin and the protective action of silymarin on the dry mass and class pattern of hepatocytes are discussed.

Topics: Amanitins; Animals; Biometry; Chemical and Drug Induced Liver Injury; Flavonoids; Liver; Male; Microscopy, Interference; Oligopeptides; Phalloidine; Rats; Silymarin

Topics: Alanine Transaminase; Alcohol Oxidoreductases; Amanitins; Anesthetics, Local; Animals; Aspartate Aminotransferases; Body Temperature; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Dogs; Female; Flavonoids; L-Lactate Dehydrogenase; Lethal Dose 50; Male; Mice; Phalloidine; Rabbits; Rats; Silymarin; Sorbitol; Time Factors; Vascular Resistance