Gyromitrin - Mechanism of Toxicity

Mechanism of Toxicity

Gyromitrin is a volatile water-soluble hydrazine compound hydrolyzed in the body into monomethylhydrazine (MMH). 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 regulated oxidative metabolism which via reactive nitrosamide intermediates leads to formation of methyl radicals which lead to liver necrosis. 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. 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.