A 24-year-old man comes to emergency department complaining of abdominal pain, vomiting, and severe watery diarrhea. He recently returned from a camping trip and admits to eating wild mushrooms that he collected in the woods. His past medical history is insignificant and he takes no medications. He does not use illicit drugs. On physical examination, he is ill-appearing and jaundiced. His liver edge is soft, tender, and palpable 4 cm below the right costal margin. Laboratory tests are significant for elevated levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin. Synthesis of which of the following is most likely to be directly inhibited by the responsible toxin?
Products of eukaryotic RNA polymerases | |
RNA polymerase | Major RNA product |
RNA polymerase I | Ribosomal RNA |
RNA polymerase II | Messenger RNA |
RNA polymerase III | Transfer RNA |
Amatoxins are found in a variety of poisonous mushrooms (eg, Amanita phalloides, known as death cap) and are responsible for the majority of mushroom poisoning fatalities worldwide. Ingestion of 1 or more amatoxin-containing mushrooms is a life-threatening emergency. After absorption by the gastrointestinal tract, amatoxins are transported to the liver via the portal circulation where active transport by organic anion transporting polypeptide (OATP) and sodium taurocholate co-transporter (NTCP) concentrates the toxin within the liver cells. There, amatoxins bind to DNA-dependent RNA polymerase type II and halt mRNA synthesis, ultimately resulting in apoptosis. Other organ systems with rapid cellular turnover can also be affected in amatoxin poisoning, including the gastrointestinal tract and proximal convoluted renal tubules.
Symptoms typically start 6-24 hours after ingestion and include abdominal pain, vomiting, and severe, cholera-like diarrhea that may contain blood and mucus. Severe poisoning can lead to acute hepatic and renal failure. Urine testing for α-amanitin can confirm suspected amatoxin poisoning.
(Choice A) Acyclovir and related drugs (eg, famciclovir and valacyclovir) are inhibitors of viral DNA polymerase.
(Choice C) Ricin (from the castor oil plant Ricinus communis) is a potent toxin that inhibits protein synthesis by cleaving the rRNA component of the eukaryotic 60S subunit.
(Choice D) The only function of RNA polymerase I is to transcribe the majority of the eukaryotic ribosomal RNA components. RNA polymerase I is insensitive to amatoxins.
(Choice E) Eukaryotic RNA polymerase III transcribes transfer RNA, 5S ribosomal RNA, and other small RNA molecules. It is only weakly affected by amatoxins.
Educational objective:
Amatoxins are found in a variety of poisonous mushrooms (eg, Amanita phalloides, known as death cap) and are potent inhibitors of RNA polymerase II (halting mRNA synthesis).