Poisoning Phalloidin

The poisonous components of the most deadly mushroom Amanita phalloides (the Death Cap) are bicyclic heptapeptides which have an additional covalent bond that connects the ( -sulfur atom of an l-cysteine residue with the carbon atom in position 2 of the indole ring of the L-tryptophan. Phalloidin (or phalloidine) is the most abundant member of a whole family of related cyclic heptapeptides called phallotoxins (for a review, see Wieland1 1). These poisonous peptides, therefore, contain a cross-linking moiety consisting of L-tryptophan coupled to L-cysteine, designated tryptathionine (1), alternatively called 5-(trypto-phan-2-yl)cysteine or 2-(L-3-alanylsulfenyl)-L-tryptophan (Scheme 1). 

Another class of toxins produced by some mushrooms consists of polypeptides, particularly amanitin and phalloidin. These substances are stable to heating (cooking). They are systemic poisons that attack cells of various organs, including the heart and liver. In early 1988, an organ transplant was performed on a woman in the U.S. to replace her liver, which was badly damaged from the ingestion of wild mushrooms that she and a companion had mistakenly identified as edible varieties and consumed. 

The phallotoxins 106, e.g. phalloidin, and the amatoxins 107, e.g. a-amanitin, produced by Amanita phalloides or death cup, are among the best-known peptide poisons 233). 

Many alkaloids are infamous for their strong toxicity towards animals and humans. Most of the deadly alkaloids fall into the class of neurotoxins (see above). The others have cytotoxic properties (Table 1.2). A cytotoxic effect can be generated when cell membranes are made leaky (as by saponins or steroidal alkaloids), or when elements of the cytoskeleton are inhibited. The spindle poisons vinblastine, vincristine, colchicine, and taxol are particularly famous. Actin filament formation is blocked by fungal poisons such as phalloidin from Amanita phalloides. 

Bufotenin also occurs (919) in Amanita mappa, a poisonous fungus species related to Amanita phalloides, which produces phalloidin. Such organisms can obviously carry out varied types of tryptophan metabolism. 

Cytochalasins, drugs that inhibit cellular processes that require actin polymerization and depolymerization (e.g., phagocytosis, cytokinesis, clot retraction, etc.), also act by severing and capping actin filaments. Actin filaments can be stabilized by phalloidin, derived from the poisonous mushroom Amanita phalloides. Assembly of actin filaments into bundles (as in microvilli) and three-dimensional networks is accomplished by two groups of cross-linking proteins (Table 21-6). 

O. 5 mg kg causes fiill protection of mice from death by phalloidin phallotoxins) after injection about 1 h before or, at the latest, simultaneously with 5 mg kg of the toxin. Antamanide is a competitive inhibitor of the transport system for phallotoxins and amatoxins in the parenchyma cells of the liver [Ih. Wieland, Peptides of Poisonous Amanita Mushrooms, Springer Series in Molecular Biology, Springer Ver-lag, Berlin, New York, 1986 K. Munster etal., Biochem. Biophys. Acta 1986, 860,91]. 

Muscarine from the mushroom. Amanita muse aria, has become a valuable biochemical tool for measuring peripheral effects on cholinergic receptors (see Volume 23 of this series). Each year Phalloidin from the mushroom. Amanita phalloides, causes several deaths in Europe from mushroom poisoning and has been the subject of a book by Theodor Wieland. In this volume, the subjects of alkaloids and mushrooms are brought together in a paper written by a team of experts from Poland in Alkaloids from Mushrooms. ... 

In the search for the lethal poison in A phalloides, in the absence of specific indicators, animal experiments were used, first with guinea pigs then with white mice. The fractions obtained in the work-up of extracts from the fungus were, as is the practice in pharmacology, injected into the animals under their skin (subcutaneously, s.c.) or into the veins (intravenously, i.v.) or into the abdomen (intraperitoneally, i.p). A sample was regarded active (toxic) if on its administration the mouse died within a few hours. Guided by this assay it became possible to isolate in 1937, as mentioned above, crystalline phalloidin and later several related peptides, the phallotoxins. The smallest dose which kills a 20 g... 

The poison present in the fungus most commonly responsible for cases of poisoning. Amanita phalloides, is a peptide known as phalloidin. On hydrolysis, it gives cystine and alanine, but, in addition, allohydroxy-L-proline, a diastereoisomer of the form of proline found in proteins. 

Poisoning by propargylglycine and 2-aminohexa-4,5-dienoic acid have similar symptoms as phalloidin poisoning. Although not as... 

Phalloidin is one of the poisons of the mushroom Amanita phaUoides with great toxicity. Only 50 pg are lethal for a mouse. Seven different amino acids are involved in its structure including such unusual hydroxy amino acids as hydroxy-leucine and allothreonine (T. Wieland). There is a bridge between tryptophan and the SH group of cysteine which yields hydroxy tryptophan upon hydrolysis. The formula is not reproduced here. 

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. 

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