How Toadstools affect Transcription


One of the most common and widespread mushrooms in Europe is also among the most toxic toadstools.  Amanita phalloides (familiarly known as the death cap mushroom or toadstool) grows throughout European forests, typically at the base of hardwood trees such as oaks, and is frequently encountered by picnickers and hikers in the late summer or early autumn.  The export of hardwoods to other countries has also led to the spread of Amanita phalloides to North and South America as well as Australia.  Accidental ingestion of death cap mushrooms—which resemble many edible mushrooms such as the paddy straw mushroom common in Asia—is responsible for the majority of mushroom-related illnesses and deaths in the world.  It is estimated that, without treatment, a person can die from ingesting a single death cap mushroom. 

Most of the lethal toxicity of Amanita phalloides is caused by a peptide known as alpha-amanitin, whose structure consists of eight amino acids that form a ring with a molecular weight of about 900 daltons.  Alpha-amanitin moves readily across cell membranes, and binds at very low doses (1 ug/ml) to the largest subunit of eukaryotic RNA polymerase II.  Once bound, it inhibits transcription by preventing RNA polymerase II from translocating along the DNA molecule; in other words, transcriptional elongation is blocked.  Since RNA polymerase II is responsible for the transcription of all protein-coding genes, the effects of blocking its activity are expected to be catastrophic to the organism. 

In humans, the primary effect of ingesting Amanita phalloides is seen in the liver and kidneys, particularly with the death of hepatocytes or liver cells.  These are the organs most responsible for filtering substances we ingest; liver cells are among the most actively dividing cells in adults, which also would contribute to the toxicity from blocking transcriptional elongation.  Symptoms usually do not appear until more than a day has passed, when the toxin has been absorbed from the stomach into the bloodstream; at this point, treatment options are limited.  By the fourth or fifth day after ingestion, symptoms of liver and kidney failure become evident, and about 15% of those diagnosed with Amanita poisoning die with 10 days.  Most of those who survive the poisoning have liver damage, and many require a liver transplant.  The delayed appearance of the symptoms makes Amanita poisoning difficult to diagnose and treat; this delay probably arises, at least in part, because alpha-amanitin blocks the elongation of new transcripts, so that existing transcripts and polypeptides are not affected. 

The specificity of alpha-amanitin for RNA polymerase II provided an important research tool in the early days of studying transcription.  RNA Pol I, responsible for the transcription of the ribosomal RNA genes, is insensitive to alpha-amanitin, and RNA Pol III is less sensitive than RNA Pol II to its effects.  This differential sensitivity to the toxin was early evidence that eukaryotes have different RNA polymerases which transcribe different classes of genes. 

Humans have been aware of the effects of toadstools or poisonous mushrooms for a very long time; it is thought that Roman Emperor Claudius (in 54 AD) and the Hapsburg emperor Charles VI (in 1740) died from eating Amanita phalloides.  With such a long history of human experience comes a similarly long history of folklore about toadstools, much of which is unreliable. However, one possible treatment of Amanita poisoning also comes from folk remedies; silymarin, an extract from the seeds of the milk thistle bush (Silybum marianum) that has been used for centuries to treat liver ailments, has shown promise as a therapeutic approach to Amanita poisoning.  Its possible modes of action, as well as any side effects, are not yet thoroughly understood, but it may act by competing with the toxin for update into hepatocytes.   

Find out more:

Santi et al. 2012 International Journal of Hepatology http://dx.doi.org/10.1155/2012/487480

Stickel et al. 1999 Public Health Nutrition 3: 113-124

(with assistance from Alison Meneely Wilson, RN, who has been involved with the treatment of families poisoned by Amanita phalloides)