Despite being responsible for more than 90 percent of mushroom-related deaths around the world, we still don’t know why the death cap mushroom is as deadly as it is. That makes it a bit difficult to find ways to avoid its toxic effects.
Fortunately, scientists may now have identified a substance that could act as an antidote to poisoning by the famous deadly mushroom, Amanita phalloides. In even better news, the candidate, call indocyanine green, is already FDA approved and used as a dye for medical diagnostic imaging.
a research team led by chemists Guohui Wan and Qiaoping Wang from Sun Yat-sen University in China has now shown that the chemical can reduce the potency of the major death cap toxin, α-amanitin, in human cell lines and mice, effectively blocking α-amanitin-induced cell death.
Death’s-head mushrooms are the reason you don’t just go and eat some old fungus you might pick in the woods. Originally from Europe, they can now be found all over the world. They are attractive and very similar to other edible mushroom species, and are often accidentally picked and eaten.
With no obvious signs of toxicity in their taste and a slow manifestation of symptoms, it’s far too easy to swallow a lethal dose. A few hours after eating, the patient may experience gastrointestinal symptoms that subside after a day or two, giving the false impression that everything is fine.
Everything is not good. From the moment of ingestion, the mushroom’s toxins eat away at the liver, causing symptoms that indicate serious damage to the organ. Without medical intervention — and in some cases even with acute care — death cap fungus toxins can lead to liver and sometimes kidney failure, often leading to death. They’re not called a nice day for a mushroom picnic, are they?
To get to the bottom of the toxicity of this particular fungus, the researchers chose a multi-step approach. First they used genome-wide CRISPR screening on the human cell line HAP1 to investigate the destructive impact of α-amanitin. This technique identifies genes that work together by breaking them up and looking for changes that can mark pathways in cells likely to be affected by a toxin. In 2019, for example, scientists were allowed to do so identify the molecular mechanisms of box jellyfish venom, and develop a means to interfere with its meddling.
When the team performed this screening for α-amanitin, they found that the biosynthesis of proteins called N-glycans played an important role in the cell death caused by the toxin. Digging further revealed that an enzyme called STT3B, which is required for the synthesis of N-glycans, seemed to be key to the toxicity of α-amanitin.
They then screened substances already approved by the FDA for antidote candidates. They identified a potential inhibitor of STT3B – indocyanine green.
All that remained was to test their findings. These tests were performed on multiple lines of research, including both humans and mice. Two different human cell lines – HAP1 and Hep G2 – were much more resistant to α-amanitin-induced cell death when pretreated with indocyanine green.
Next, mouse liver organoids were treated. They also showed greater resistance to cell death.
Finally, the researchers tested live mice. These were injected with the toxin and then treated with indocyanine green 4 hours later to mimic the likely treatment scenario for poisoned humans, while the researchers monitored their organs. The treated mice had less organ damage and cell death, and higher survival rates than untreated controls.
However, treatment with indocyanine green at intervals of 8 and 12 hours after poisoning lost its treatment effect, suggesting that irreversible damage occurs early and that treatment for deadly mushroom poisoning should be sought as soon as possible.
Further research needs to be conducted to determine how indocyanine green inhibits α-amanitin and to assess how safe it is to administer to humans, but these early results hold promise for an antidote in the not-too-distant future.
“general,” write the researchers“we show that by coupling whole-genome functional genomic characterization with in silico drug prediction, we can quickly define and then target medically relevant processes.”
You can read more about it identify death cap mushrooms herebut if you’re in any doubt, it’s safest not to eat the fungus you’ve found on the forest floor.
The results have been published in Nature communication.