Toxic Effects of Amanitins: Repurposing Toxicities toward New Therapeutics

Abstract

The consumption of mushrooms has become increasingly popular, partly due to their nutritional and medicinal properties. This has increased the risk of confusion during picking, and thus of intoxication. In France, about 1300 cases of intoxication are observed each year, with deaths being mostly attributed to Amanita phalloides poisoning. Among amatoxins, α- and β-amanitins are the most widely studied toxins. Hepatotoxicity is the hallmark of these compounds, leading to hepatocellular failure within three days of ingestion. The toxic mechanisms of action mainly include RNA polymerase II inhibition and oxidative stress generation, leading to hepatic cell apoptosis or necrosis depending on the doses ingested. Currently, there is no international consensus concerning Amanita phalloides poisoning management. However, antidotes with antioxidant properties remain the most effective therapeutics to date suggesting the predominant role of oxidative stress in the pathophysiology. The partially elucidated mechanisms of action may reveal a suitable target for the development of an antidote. The aim of this review is to present an overview of the knowledge on amanitins, including the latest advances that could allow the proposal of new innovative and effective therapeutics.

A therapeutic oxygen carrier isolated from Arenicola marina decreases amanitin-induced hepatotoxicity

“…Our present results can be considered with regard to the currently available treatments for Amanita phalloides poisoning. The death rate associated with this poisoning is still high (between 10% and 20%), despite the use of antidotes such as penicillins, thioctic acid, N-acetylcysteine, vitamin C, silymarin, and silibinin (Enjalbert et al, 2002;Escudié et al, 2007;Ganzert et al, 2005;Le Daré et al, 2021). The J o u r n a l P r e -p r o o f fact that none of these compounds are highly effective means that Amanita phalloides poisoning is still a challenging medical emergency.…”

Possibilities of Using Macrolepiota procera in the Production of Prohealth Food and in Medicine

“…Approximately 30 minutes after consumption, it passes from the digestive system into the blood, and with it is distributed throughout the body. About 60% of α -AMA accumulates in the liver and causes severe damage to this organ [ 25 , 26 ].…”

Rationally Designed Amanitins Achieve Enhanced Cytotoxicity

“…Given the high significance of α-amanitin to fundamental and applied science, new analogues would be of great value, as highlighted in a 2021 review. 31 Yet, the extensive array of interactions between α-amanitin and Pol II makes designing amatoxins with increased toxicity neither trivial nor obvious. To date, most antecedent reports have been limited to amatoxins obtained by modifying or degrading the natural product or constructing analogues from natural amino acids.…”