phalloidine and Chemical-and-Drug-Induced-Liver-Injury

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

Topics: Animals; Calcium; Carbon Tetrachloride; Cell Membrane; Chemical and Drug Induced Liver Injury; Galactosamine; In Vitro Techniques; Liver; Liver Diseases; Necrosis; Phalloidine; Rats

The pharmacological actions of (+)-cyanidanol-3 [(+)-flavan-3,3',4',5,7-pentol, (+)-catechin, Catergen) in various experimental liver diseases are described according to the recent available literature. On this basis the hepatoprotective activity of the drug is due to its stabilizing effect on biological membranes and its specific inhibitory activity on the Fe-ADP-, CCl4- and CBrCl3- stimulated lipoperoxidation in vitro and in vivo.

Topics: Animals; Benzopyrans; Catechin; Chemical and Drug Induced Liver Injury; Galactosamine; Lipid Peroxides; Liver; Liver Diseases; Membranes; Phalloidine

This study utilized pharmacological activation of Nrf2 with oleanolic acid (OA, 22.5mg/kg, sc for 4 days) and the genetic alteration of Nrf2 (Nrf2-null, wild-type, and Keap1-HKO mice) to examine the role of Nrf2 in protection against phalloidin hepatotoxicity. Mice were given phalloidin (1.5mg/kg, ip for 8h) to examine liver injury and the expression of toxicity-related genes. Phalloidin increased serum enzyme activities and caused extensive hepatic hemorrhage and necrosis in Nrf2-null and wild-type mice, but less injury was seen in Keap1-HKO mice and OA-pretreated mice. Phalloidin increased the expression of neutrophil-specific chemokine mKC and MIP-2 in Nrf2-null and WT mice, but such increases were attenuated in Keap1-HKO and OA-pretreated mice. Phalloidin increased, while Nrf2 activation attenuated, the expression of genes involved in acute-phase response (Ho-1) and DNA-damage response genes (Gadd45 and Chop10). Phalloidin is taken up by hepatocytes through Oatp1b2, but there was no difference in basal and phalloidin-induced Oatp1b2 expression among Nrf2-null, wild-type, and Keap1-HKO mice. In contrast, OA decreased phalloidin-induced Oatp1b2. Phalloidin activated MAPK signaling (p-JNK), which was attenuated by activation of Nrf2. In conclusion, this study demonstrates that protection against phalloidin hepatotoxicity by OA involves activation of Nrf2 and suppression of Oatp1b2.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytoprotection; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Gene Expression Regulation; Inflammation Mediators; Kelch-Like ECH-Associated Protein 1; Lipid Peroxidation; Liver; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oleanolic Acid; Organic Anion Transporters, Sodium-Independent; Phalloidine; RNA, Messenger; Signal Transduction; Solute Carrier Organic Anion Transporter Family Member 1B3

Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (-60%) and TCA-stimulated bile flow (-55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (<5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous bile acids. When highly choleretic bile acids, - ursodeoxycholic (UDCA) and dehydrocholic acid (DHCA) - were administered, they were found less efficient than BALU-1 in preventing phalloidin-induced cholestasis. Biliary phalloidin elimination was low but it was increased by BALU-1>TCA>DHCA>UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.

Topics: Animals; Bile Acids and Salts; Biological Transport; Chemical and Drug Induced Liver Injury; Infusions, Intravenous; Liver; Male; Phalloidine; Rats; Rats, Wistar

The present study examined the possible involvement of endogenous cyclooxygenase-derived factors in the lethality and hepatic hemorrhagic necrosis induced by phalloidin. Mice were pretreated with indomethacin, aspirin or ibuprofen (all inhibitors of cyclooxygenase) and injected with phalloidin (2 mg/kg). The toxin induced 75% lethality and caused severe hemorrhagic necrosis of the liver associated with increased serum levels of AST and ALT. Indomethacin completely prevented the mortality and hepatic damage elicited by phalloidin as judged by morphologic analysis and serum AST and ALT release. The in vitro addition of indomethacin to suspensions of freshly-isolated hepatocytes decreased plasma membrane bleb formation induced by phalloidin. In contrast to indomethacin, aspirin and ibuprofen did not influence phalloidin toxicity in vivo. These results suggest that inhibition of prostanoids per se may not be the sole mechanism of protection by indomethacin.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Aspirin; Chemical and Drug Induced Liver Injury; Female; Ibuprofen; Indomethacin; Liver; Liver Diseases; Mice; Microscopy, Electron; Phalloidine; Time Factors

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

Interleukin 2 (IL-2) is a potent cytokine with diverse effects, including the ability to stimulate lymphocyte differentiation into cells capable of lysing tumor. Its therapeutic efficacy is limited because of side effects such as breakdown of the microvascular barrier and edema. Control of the microvascular barrier is in part regulated by endothelial cell cytoskeletal contractile proteins. This study tests whether the cyclopeptides that maintain actin filament organization and distribution and reduce macromolecular flux across the endothelial cell junction in vitro would similarly maintain barrier tightness and prevent early edema produced by IL-2 in vivo. Anesthetized rats were treated at 30-min periods with intravenous saline (0.5 ml, n = 41), phalloidin (20 micrograms in 0.5 ml, n = 21), or antamanide, (20 micrograms in 0.5 ml, n = 21), starting 30 min before the 1-h infusion of 10(6) U of recombinant human IL-2 or saline. Six hours after the start of IL-2, there was edema in the saline/IL-2 group, as measured by increased wet-to-dry ratios (W/D) in the lungs, heart, and kidney. With saline/IL-2, bronchoalveolar lavage (BAL) fluid contained an elevated protein concentration and higher plasma thromboxane levels compared with controls. The number of neutrophils sequestered in the lungs was more than twice that of saline controls. Phalloidin significantly attenuated edema in lung and reduced BAL protein leak. Antamanide treatment was as effective in limiting lung and heart edema, but, in contrast to phalloidin, antamanide prevented kidney edema and did not lead to an alteration in the liver W/D. Antamanide also prevented BAL fluid protein leak.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Capillary Permeability; Chemical and Drug Induced Liver Injury; Edema; Edema, Cardiac; Interleukin-2; Kidney Diseases; Liver Diseases; Male; Peptides, Cyclic; Phalloidine; Pulmonary Edema; Rats; Rats, Inbred Strains; Thromboxane B2

For the study of structure-activity relationships, the antihepatotoxic wedelolactone (7-methoxy-5,11,12-trihydroxy-coumestan) and 6 coumestan derivatives were synthesized by the application of a modified method of Wanzlich. An evaluation of the biological characteristics of the synthetic compounds and acuminatin from Musa acuminata showed that most of the wedelolactone derivatives significantly protected primary cultured liver cells from the toxicity of CCl4, galactosamine (Galc), and phalloidin, and strongly inhibited the activity of 5-lipoxygenase in porcine leukocytes. The hepatocyte protective activity was dependent on the C-7 substitution with pharmacological efficacy decreasing in the following order: EtO greater than MeO greater than OH greater than CH3(CH2)9. In addition, a free OH at C-5 of the wedelolactone molecule was shown to be important in protecting hepatocytes from CCl4 and Galc damage. Similar observation regarding the effect of C-7 substitution in wedelolactone was obtained in the 5-lipoxygenase test. In general, an increase in the lipophilicity in ring A increased the inhibition of 5-lipoxygenase activity. The synthetic wedelolactone was also found to have stimulatory effect on the RNA synthesis in isolated nuclei from hepatocytes.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Arachidonate Lipoxygenases; Carbon Tetrachloride Poisoning; Cell Survival; Chemical and Drug Induced Liver Injury; Coumarins; In Vitro Techniques; Leukocytes; Lipoxygenase Inhibitors; Liver; Phalloidine; Rats; RNA; Swine

A single i.p. dose of phalloidin, 0.75 or 1 mg/kg body weight, induced peliosis hepatis-like lesion (PHLL) at 3 h after injection to mice. Pretreatment with various doses of testosterone propionate for 7 days enhanced phalloidin-induced PHLL. Other anabolic steroids, methyltestosterone, methandriol. fluoxymesterone and oxymetholone had no effect.

Topics: Androgens; Animals; Chemical and Drug Induced Liver Injury; Drug Synergism; Female; Liver; Mice; Mice, Inbred C3H; Oligopeptides; Phalloidine; Testosterone

Exposure of freshly isolated hepatocytes to phalloidin produced blebs on their surfaces: this phenomenon was time- and dose-dependent and irreversible. When hepatocytes were pretreated with somatostatin or with some of its synthetic analogues, formation of blebs was dramatically reduced. This cytoprotective effect was dose-dependent: the dose-response profiles enabled the determination of the CD50 values, i.e., the concentrations of analogues that yielded 50% cytoprotection. The analogues with sequences of amino acids in the retro form, compared to those in somatostatin-14, exhibited higher cytoprotection; the retro hexapeptide, cyclo(-Phe-Thr-Lys-D-Trp-Phe-D-Pro-), was 27 times more active than somatostatin-14. Specificity of cytoprotection was examined by pretreating hepatocytes with biologically active peptide hormones prior to exposure to phalloidin. On a molar basis, prolactin and thyroid-stimulating hormone possessed activity comparable to that of somatostatin-14, whereas glucagon was twice as active. Insulin, vitamin A and propranolol exercised less than 10% protection. The synthetic analogues of somatostatin are potent protective agents against cell lesions induced by phalloidin. Formation of blebs on hepatocytes by toxins and their prevention by agents of interest may serve as a suitable morphological assay for screening of cytotoxicity and cytoprotection.

Topics: Animals; Cell Membrane; Cell Survival; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; In Vitro Techniques; Liver; Male; Oligopeptides; Peptides, Cyclic; Phalloidine; Rats; Somatostatin; Structure-Activity Relationship; Time Factors

Topics: Actins; Animals; Biological Transport; Calcium; Cells, Cultured; Chemical and Drug Induced Liver Injury; Liver; Mitochondria, Liver; Oligopeptides; Phalloidine; Rats

Topics: Amphotericin B; Animals; Bile Acids and Salts; Calcium; Chemical and Drug Induced Liver Injury; In Vitro Techniques; Liver; Male; Mycotoxins; Oligopeptides; Peptides, Cyclic; Phalloidine; Rats; Rats, Inbred Strains; Rifampin; Sodium; Transaminases; Valinomycin

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

Phalloidin, one of the main toxins of Amanita phalloides, induced hepatotoxicity in female Wistar rats at 0.9 mg/kg dose i.p. Biliary secretion was selectively inhibited after 3h, but was restored after 24 h. Phalloidin also induced a cytolytic lesion, but not a fatty liver, as in alpha-amanitin intoxication. Propranolol pretreatment (30 min prior to phalloidin injection) did not afford protection against hepatotoxicity, but increased alkaline phosphatase, 5'-nucleotidase and aminotransferase activities.

Topics: Animals; Bile; Chemical and Drug Induced Liver Injury; Cholestasis; Female; Lipid Metabolism; Liver; Oligopeptides; Phalloidine; Propranolol; Rats; Transaminases

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

Plasma protein profiles were investigated electrophoretically in rats with aminonucleoside-induced glomerular damage, uranyl-nitrate-induced tubular damage, phalloidin-induced hepatocyte membrane damage, adjuvant arthritis as a model of chronic inflammation, and phenyl isothiocyanate pleurisy as a model of acute inflammation. Characteristic profiles were observed for each experimental disease, and their development and seriousness could be evaluated. Similar studies are already routinely used in clinical investigations of human plasma.

Topics: Animals; Blood Proteins; Chemical and Drug Induced Liver Injury; Electrophoresis, Cellulose Acetate; Isothiocyanates; Kidney Diseases; Liver Diseases; Phalloidine; Pleurisy; Puromycin Aminonucleoside; Rats; Rodent Diseases; Thiocyanates; Uranyl Nitrate

Isolated hepatocytes, prepared from 5 day old rats, from regenerating livers of from livers after poisoning with carbon tetrachloride, are less sensitive to phalloidin in vitro than hepatocytes from untreated adult controls. The time course of the reduced susceptibility to phalloidin was compared with the ability of hepatocytes to take up bile acids under various conditions. SDS-electrophoresis of cell lysates gave no evidence for decreased levels of actin in cells with reduced sensitivity to phalloidin. In contrast, there was a good relationship between the active uptake of bile acids and the sensitivity of hepatocytes to phalloidin. The decreased response of hepatocytes from baby rats, from regenerating livers or from poisoned livers to phalloidin is more probably related to differences in phalloidin uptake than to a reduced endowment with microfilamentous structures.

Topics: Actins; Age Factors; Animals; Animals, Newborn; Bile Acids and Salts; Carbon Tetrachloride Poisoning; Cells; Chemical and Drug Induced Liver Injury; Liver Regeneration; Myosins; Oligopeptides; Phalloidine; Proteins; Rats

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

Topics: Animals; Chemical and Drug Induced Liver Injury; Female; Flavonoids; Liver; Mice; Oligopeptides; Phalloidine; Silymarin; Time Factors

Continuous intraperitoneal administration of phalloidin (0.5 mg/kg body weight/day) leads to an alteration of intracellular contractile acto-myosinfilaments in rat liver. The hepatocytes show an accumulation of fibrillar material with some loss of contractile function of the pericanalicular web. Biochemically an increase of serum transaminases and alkaline phosphatase occurs. Histochemically the liver exhibitis changes in the distribution of some hepatocellular enzymes. The influence of the flavonoid (+)-cyanidanol-3 on these phalloidin-induced lesions was studied by histochemical, immunofluorescence and biochemical methods. The results imply, that (+)-cyanidanol-3 is probably protecting the plasma membrane of hepatocytes and therefore reduces the entrance of phalloidin into the cytoplasm. In addition an increased activity of the reticuloendothelial system was observed, perhaps resulting from the flavonoid administration. Both effects could be discussed as mechanisms of flavonoid action in the liver.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cholesterol; Flavonoids; Liver; Oligopeptides; Phalloidine; Rats

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

Histochemical and histoenzymological studies carried out on liver slices of the mouse show that silybin both as prophylactic and curative treatment, inhibits the disorders of metabolic activity brought about by phallodine and maintains enzymatic activities at levels comparable with those of the control animals. Silybin, when administered alone, produces only minor changes in activities. As with silymarin, the only notable effect is an increased activity of alkaline phosphatase. The mode of action of these two substances appears to be the same.

Topics: Animals; Chemical and Drug Induced Liver Injury; Flavonoids; Histocytochemistry; Male; Mice; Oligopeptides; Phalloidine; Silymarin

Topics: Animals; Chemical and Drug Induced Liver Injury; Hemorrhage; Intestine, Small; Lung; Necrosis; Oligopeptides; Phalloidine; Rats; Shock, Hemorrhagic

Topics: Animals; Animals, Newborn; Chemical and Drug Induced Liver Injury; Hemorrhage; Liver; Liver Regeneration; Male; Necrosis; Oligopeptides; Phalloidine; Rats; Thymidine; Tritium

Topics: Animals; Arginine; Chemical and Drug Induced Liver Injury; Liver; Male; Mushroom Poisoning; Oligopeptides; Perfusion; Phalloidine; Potassium Deficiency; Rats

Topics: Adolescent; Adult; Aged; Animals; Bile; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Female; Flavonoids; Hepatitis; Hepatitis B; Humans; Liver; Liver Cirrhosis; Liver Diseases; Liver Function Tests; Male; Middle Aged; Phalloidine; Rabbits; Silymarin

The K+ release from the isolated perfused rat liver induced by phalloidin was strongly inhibited on raising the Mg2+ concentration of the perfusion medium from 0.5-40mM while, in contrast, the phalloidin induced swelling of the organ and the vasuolisation of the liver tissue was not affected.

Topics: Animals; Biological Transport; Chemical and Drug Induced Liver Injury; Edema; In Vitro Techniques; Liver; Magnesium; Male; Oligopeptides; Organ Size; Phalloidine; Potassium; Rats

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

The hepatoprotective action of silymarin, the active principle extracted from the fruit of Silybum marianum (L.) Gaertn., in animals (dogs, rabbits, rats, mice) intoxicated with phalloidine is evident, both after protective and curative treatment. A dose of 15 mg/kg of silymarin protects every animal when given 60 min before the toxin. When injected 10 mim after phalloidine, a dose of 100 mg/kg of silymarin again provides total protection. However, as the time span between administration of the toxic substance and start of treatment increases, so the efficacy of silymarin decreases; after 30 min its curative effect is negligible. The histochemical and histoenzymological studies show that during intoxication of the mice by phalloidine, silymarin inhibits the effect of the toxic substance and regulates the functions of the hepatocyte, when given either 60 min before or 10 min after phalloidine.

Topics: Adenosine Triphosphatases; Animals; Carbohydrate Metabolism; Chemical and Drug Induced Liver Injury; Citric Acid Cycle; Dogs; Female; Flavonoids; Glycerolphosphate Dehydrogenase; Histocytochemistry; L-Lactate Dehydrogenase; Lethal Dose 50; Lipid Metabolism; Liver; Male; Mice; Oligopeptides; Phalloidine; Rabbits; Rats; Silymarin; Time Factors

Microsomes were prepared from perfused rat livers after different perfusion procedures. The yield of microsomal protein and the kinetic data (Km, Vmax) of glucose-6-phosphatase (3.1.3.9) and esterase (3.1.1.1) activities were analysed in each preparation. No marked differences were detected between conventionally prepared liver microsomes and those from livers perfused 1 hr with an erythrocytes-free medium under the conditions of open outflow. If the outflow pressure was increased artificially, the yield of microsomal protein decreased. The Vmax of both enzymes was markedly increased, whereas the Km values remained unchanged. The same microsomal alterations occurred when perfused rat livers were poisoned with phalloidin in vitro under the condition of open outflow. Our findings indicate that microsomal alterations in livers from poisoned animals might be due to microcirculatory disturbances, and not primary effects of the toxin on the endoplasmatic reticulum.

Topics: Animals; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum; Esterases; Glucose-6-Phosphatase; In Vitro Techniques; Kinetics; Liver; Liver Circulation; Male; Microcirculation; Microsomes, Liver; Oligopeptides; Organ Size; Perfusion; Phalloidine; Pressure; Rats; Time Factors

Topics: Actins; Animals; Bile Ducts, Intrahepatic; Chemical and Drug Induced Liver Injury; Cytoplasm; Drug Administration Schedule; Humans; Hyperplasia; Inclusion Bodies; Liver; Liver Diseases; Male; Oligopeptides; Phalloidine; Rats

1. Thioctic acid used clinically in poisoning by A. phalloides, protected perfused livers and also isolated hepatocytes against phalloidin, when given in high concentrations. 2. Some SH-compounds like coenzyme A, dimercaprol, cysteine and cysteamine were found to be protective in different concentrations. 3. Rifampicin protects mice against lethal doses of phalloidin, and inhibits poisoning of isolated hepatocytes at low concentrations. 4. Some choleretic drugs like dehydrocholate, temoebilin (extr. cucumae xanth.), ethacrynic acid influenced phalloidin poisoning by inhibition of binding. 5. Doses of 0.2 to 4.0 mg dexamethasone added to 100 ml of perfusion medium did not protect perfused rat livers against 0.5 mg phalloidin. 6. Pretreatment of female rats with estrogens effected protection against phalloidin in vivo. The same procedure resulted in moderate decrease of phalloidin effects when the livers of pretreated animals were poisoned in vitro. In male rats estrogen pretreatment was less effective. Castration did not augment the protective effect. 7. Secophalloidin, a biologically inactive derivative, did not influence phalloidin poisoning in perfused livers, even when applied in excessive concentrations. 8. Concanavalin A, probably bound in the neighborhood of binding sites for phalloidin, did not protect perfused livers against phalloidin. 9 Diethyldithiocarbamate, a compound protecting livers against carbon tetrachloride and halothane, was ineffective in phalloidin poisoning. 10. Further protective actions of Evans blue, of some phenanthrolines and of EDTA are discussed. 11. Pretreatment of animals with hepatotoxic compounds (CCl4, CHCl3, cinchophen) decreased the toxicity of phalloidin in vivo. Possible mechanisms are discussed.

Topics: Animals; Chelating Agents; Chemical and Drug Induced Liver Injury; Chloroform; Cholagogues and Choleretics; Coenzyme A; Concanavalin A; Cysteamine; Cysteine; Dexamethasone; Dimercaprol; Estradiol; Female; Male; Oligopeptides; Phalloidine; Rats; Rifampin; Sulfhydryl Compounds; Thioctic Acid

Phalloidin produces marked protrusions on the surface of isolated hepatocytes prepared from rat livers. This typical in-vitro effect of the mushroom toxin is prevented or inhibited by preincubation with disilybin. The antagonistic effect depends on the concentration of disilybin and might be caused by an inhibition of phalloidin binding.

Topics: Animals; Chemical and Drug Induced Liver Injury; Flavonoids; Liver; Microscopy, Electron, Scanning; Microscopy, Phase-Contrast; Oligopeptides; Perfusion; Phalloidine; Protein Binding; 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

The protective effects of antamanide, O-carboxy-methyl-Tyr5-antamanide and of Tyr6-antamanide-monosulfate against phalloidin were tested in perfused rat livers. None of the applied doses was able to inhibit swelling and potassium loss of poisoned livers completely. In the perfused liver antamanide preferentially inhibited swelling but not potassium loss. O-Carboxymethyl-Tyr5-antamanide protected isolated hepatocytes against phalloidin. The different effects of antamanide derivatives in perfused livers and in vivo are discussed.

Topics: Animals; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Hepatomegaly; Liver; Male; Microscopy, Electron, Scanning; Oligopeptides; Peptides, Cyclic; Perfusion; Phalloidine; Potassium; Rats

Topics: Animals; Cell Membrane; Cell Membrane Permeability; Chemical and Drug Induced Liver Injury; Dextrans; Endocytosis; Hydrogen-Ion Concentration; Male; Oligopeptides; Perfusion; Phalloidine; Potassium; Povidone; Rats; Water