amanitins and Necrosis

The activation of the death receptors, tumor necrosis factor-receptor-1 (TNF-R1) or CD95, is a hallmark of inflammatory or viral liver disease. In different murine in vivo models, we found that livers depleted of gamma-glutamyl-cysteinyl-glycine (GSH) by endogenous enzymatic conjugation after phorone treatment were resistant against death receptor-elicited injury as assessed by transaminase release and histopathology. In apoptotic models initiated by engagement of CD95, or by injection of TNF or lipopolysaccharide into galactosamine-sensitized mice, hepatic caspase-3-like proteases were not activated in the GSH-depleted state. Under GSH depletion, also caspase-independent, TNF-R1-mediated injury (high-dose actinomycin D or alpha-amanitin), as well as necrotic hepatotoxicity (high-dose lipopolysaccharide) were entirely blocked. In the T-cell-dependent model of concanavalin A-induced hepatotoxicity, GSH depletion resulted in a suppression of interferon-gamma release, delay of systemic TNF release, hepatic nuclear factor-kappaB activation, and an abrogation of sinusoidal endothelial cell detachment as assessed by electron microscopy. When GSH depletion was initiated 3 hours after concanavalin A injection, ie, after the peak of early pro-inflammatory cytokines, livers were still protected. We conclude that sufficient hepatic GSH levels are a prerequisite for the execution of death receptor-mediated hepatocyte demise.

Topics: Amanitins; Animals; Antigens, CD; Apoptosis; Caspases; Cell Death; Concanavalin A; Cytokines; Dactinomycin; Dose-Response Relationship, Drug; Glutathione; Liver; Male; Mice; Mice, Inbred BALB C; Necrosis; Nucleic Acid Synthesis Inhibitors; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Shock, Septic

Twelve patients with Galerina Autumnalis (GA) poisoning were treated. Amatoxin and phallotoxin are the principal toxins of GA. After absorption from intestine into the liver, the toxins combine with RNA polymerase, resulting in block of messenger (mRNA) synthesis, hepatocellular damage, hepatitis, hepatic necrosis, serious coagulation abnormalities and DIC. The clinical characteristics are long latent period, short period of "pseudo-remission" and serious liver dysfunction. These were pathologically confirmed by autopsy. Our experiences with this poisoning are as follows: treatment should be carried out as early as possible, especially with gastric lavage and catharsis and special attention paid to the "pseudo-remission".

Topics: Adolescent; Adult; Agaricales; Amanitins; Child; Female; Gastric Lavage; Humans; Liver; Male; Mushroom Poisoning; Necrosis

In mice poisoned by alpha-amanitin nuclear changes typical of this toxin were observed in beta-cells of pancreatic islets. The lesions became progressively more severe and at 48 h after toxin injection some cells were necrotic. The damage to these cells could have implications in the changes in glycogen metabolism which occur after alpha-aminitin poisoning.

Topics: Amanitins; Animals; Cell Nucleus; Glycogen; Islets of Langerhans; Male; Mice; Microscopy, Electron; Necrosis

The serum of patients suffering from Amanita phalloides poisoning was analysed in order to determine whether amanitines, which are the principal toxins of this fungus, were still present in the blood at the time of hospitalisation. In addition, the authors measured the concentrations of amanitines in the blood of dogs at different intervals after the ingestion of a fatal dose of Amanita phalloides. Amanitines were detected in the serum of 9 patients out of 16. This discovery, together with the finding that, in the dog, very low concentrations of amanitines in the blood are associated with fatal cellular lesions, suggests the need for very prompt action in order to eliminate these toxins from the blood as soon as the diagnosis of poisoning is suspected.

Topics: Amanita; Amanitins; Animals; Dogs; Humans; Liver; Mushroom Poisoning; Necrosis