Hepatocytes phalloidin

Death cap mushroom. Responsible for > 90% of mushroom deaths in the UK. Contains the peptides, amanitine and phalloidine. Hepato-toxic a-amanitine is the major toxic component. Direct attack on hepatocyte nuclei. Vomiting 8-12 h post-ingestion cramping abdominal pain diarrhoea. 2-3 days latent period then jaundice, circulatory collapse, haemorrhage, death. Death rate 30% in best hands . 

It has been shown in experimental animals that pectenotoxin-1 (PTX-1) is hepatotoxic and induces rapid necrosis of hepatocytes, with a pathological action similar to that of phalloidin. In rats intraperitonially injected with PTXs, the liver finally appears granulated and the hepatocytes contain many vacuoles. 

A cyclo-nonapeptide, isolated from linseed by Kaufmann and Tobschirbel [48] which also prevents the uptake of phalloidin (and other substances) by hepatocytes, cyclolinopeptide A, shows a certain similarity with AA in its amino acid sequence (Fig. 20) but does not form alkali-metal complexes. With the accumulation of aromatic amino acids between proline residues as an active region in mind, Kessler et al. designed some smaller cyclopeptides of which one, c(D-ProPhePheProPhePhe), exhibited somewhat stronger protection and a second less related one, called 008, showed even better protection of liver cells against phalloidin than antamanide [49]. 

In contrast to amatoxins, phalloidin poisoning in laboratory animals is seen only after parenteral application. From this it was concluded that the absorption rate of phallotoxins after oral administration must be rather low. Besides this explanation however, one has to consider that the target protein of phallotoxins, actin in non-muscle cells and particularly in hepatocytes, is present in a ca. 10 times higher concentration (5 x lO " M) than RNA-po-lymerases II (5 x lO M). Correspondingly, the intracellular threshold for toxic events caused by phallotoxins is distinctly higher than that for amatoxins and may not be reached after enteral administrations. This may explain why phallotoxins fail to contribute to human Amanita poisoning. 

In isolated hepatocytes the first toxic lesion is a change in cell shape. About 10 minutes after administration of phalloidin to the medium hepatocytes develop numerous blebs on their surface (11). We compared the kinetics of bleb formation in vivo with the kinetics of actin polymerization from the thymosin (34 complex in vitro, and found that the two processes develop at a comparable rate. Since polymerization occurs at a rate somewhat faster than the development of surface blebbing in vivo, the morphological lesions in the... 

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