Gyromitrin is a toxin and carcinogen present in several members of the fungal genus Gyromitra, like G. esculenta. Its formula is C4H8N2O. It is unstable and is easily hydrolyzed to the toxic compound monomethylhydrazine CH3NHNH2. Monomethylhydrazine acts on the central nervous system and interferes with the normal use and function of vitamin B6. Poisoning results in nausea, stomach cramps, and diarrhea, while severe poisoning can result in convulsions, jaundice, or even coma or death. Exposure to monomethylhydrazine has been shown to be carcinogenic in small mammals.
History Poisonings related to consumption of the false morel Gyromitra esculenta, a highly regarded fungus eaten mainly in Finland and by some in parts of Europe and North America, had been reported for at least a hundred years. Experts speculated the reaction was more of an allergic one specific to the consumer, or a misidentification, rather than innate toxicity of the fungus, due to the wide range in effects seen. Some would suffer severely or perish while others exhibited no symptoms after eating similar amounts of mushrooms from the same dish. Yet others would be poisoned after previously eating the fungus for many years without ill-effects. In 1885, Böhm and Külz described helvellic acid, an oily substance they believed to be responsible for the toxicity of the fungus. The identity of the toxic constituents of Gyromitra species eluded researchers until 1968, when N-methyl-N-formylhydrazone was isolated by German scientists List and Luft and named gyromitrin. Each kilogram of fresh false morel had between 1.2 and 1.6 grams of the compound.
Mechanism of toxicity
Gyromitrin is a volatile, water-soluble hydrazine compound that is rapidly metabolized into monomethylhydrazine (MMH) through the intermediate N-methyl-N-formylhydrazine.
Other N-methyl-N-formylhydrazone derivatives have been isolated in subsequent research, although they are present in smaller amounts. These other compounds would also produce monomethylhydrazine when hydrolyzed, although it remains unclear how much each contributes to the false morel's toxicity. The toxins react with pyridoxal 5-phosphate—the activated form of pyridoxine—and form a hydrazone. This reduces production of the neurotransmitter GABA via decreased activity of glutamic acid decarboxylase, which gives rise to the neurological symptoms. MMH also causes oxidative stress leading to methemoglobinemia. Additionally during the metabolism of MMH, N-methyl-N-formylhydrazine is produced; this then undergoes cytochrome P450 oxidative metabolism which produces large amounts of hepatotoxic free radicals in a manner similar to the metabolism of carbon tetrachloride. Inhibition of diamine oxidase (histaminase) elevates histamine levels, resulting in headaches, nausea, vomiting, and abdominal pain. Giving pyridoxine to rats poisoned with gyromitrin inhibited seizures, but did not prevent liver damage. The toxicity of gyromitrin varies greatly according to the animal species being tested. Tests of administering gyromitrin to mice to observe the correlation between the formation of MMH and stomach pH have been performed. Higher levels of formed MMH were observed in the stomachs of the mice than were observed in control tests under less acidic conditions. The conclusions drawn were that the formation of MMH in a stomach is likely a result of acid hydrolysis of gyromitrin rather than enzymatic metabolism. Based on this animal experimentation, it is reasonable to infer that a more acidic stomach environment would transform more gyromitrin into MMH, independent of the species in which the reaction is occurring. The median lethal dose (LD50) is 244 mg/kg in mice, 50–70 mg/kg in rabbits, and 30–50 mg/kg in humans. The toxicity is largely due to the MMH that is created; about 35% of ingested gyromitrin is transformed to MMH. Based on this conversion, the LD50 of MMH in humans has been estimated to be 1.6–4.8 mg/kg in children, and 4.8–8 mg/kg in adults.
Occurrence and removal
Several Gyromitra species are traditionally considered very good edibles and several steps are available to remove gyromitrin from these mushrooms and allow their consumption. For North America, the toxin has been reliably reported from the species G. esculenta, G. gigas, and G. fastigiata. Species in which gyromitrin's presence is suspected, but not proven, include G. californica, G. caroliniana, G. korfii, and G. sphaerospora, in addition to Disciotis venosa and Sarcosphaera coronaria. The possible presence of the toxin renders these species "suspected, dangerous, or not recommended" for consumption. Gyromitrin content can differ greatly in different populations of the same species. For example, G. esculenta collected from Europe is "almost uniformly toxic", compared to rarer reports of toxicity from specimens collected from the US west of the Rocky Mountains. A 1985 study reported that the stems of G. esculenta contained twice as much gyromitrin as the cap, and that mushrooms collected at higher altitudes contained less of the toxin than those collected at lower altitudes. The gyromitrin content in false morels has been reported to be in the range of 40–732 milligrams of gyromitrin per kilogram of mushrooms (wet weight). Gyromitrin is volatile and water soluble, and can be mostly removed from the mushrooms by cutting them to small pieces and repeatedly boiling them in copious amounts of water under good ventilation. Prolonged periods of air drying also reduces levels of the toxin. In the US, there are typically between 30 and 100 cases of gyromitrin poisoning requiring medical attention. The mortality rate for cases worldwide is about 10%.
Detection The early methods developed for the determination of gyromitrin concentration in mushroom tissue were based on thin-layer chromatography and spectrofluorometry, or the electrochemical oxidation of hydrazine. These methods require large amounts of sample, are labor-intensive and unspecific. A 2006 study reported an analytical method based on gas chromatography-mass spectrometry with detection levels at the parts per billion level. The method, which involves acid hydrolysis of gyromitrin followed by derivatization with pentafluorobenzoyl chloride, has a minimum detectable concentration equivalent to 0.3 microgram of gyromitrin per gram of dry matter.
Identification
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