Cycasin is a

carcinogenic A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...

and

neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

glucoside A glucoside is a glycoside that is chemically derived from glucose. Glucosides are common in plants, but rare in animals. Glucose is produced when a glucoside is hydrolysed by purely chemical means, or decomposed by fermentation or enzymes. Th ...

found in

cycad Cycads are seed plants that typically have a stout and woody (ligneous) trunk (botany), trunk with a crown (botany), crown of large, hard, stiff, evergreen and (usually) pinnate leaves. The species are dioecious, that is, individual plants o ...

s such as ''

Cycas revoluta ''Cycas revoluta'' (Sotetsu apanese ソテツ sago cycad, sago palm, king sago, Japanese sago palm) is a species of gymnosperm in the family Cycadaceae, native to southern Japan including the Ryukyu Islands. It is one of several species used f ...

'' and ''

Zamia pumila ''Zamia pumila'', commonly known as guáyiga or guáyara in Spanish, is a small, tough, woody cycad native to the Greater Antilles. ''Z. pumila'' was the first species described for the genus and, therefore, is the type species for the genus ''Za ...

''. Symptoms of poisoning include vomiting, diarrhea, weakness, seizures, and

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

. In metabolic conditions, cycasin is hydrolyzed into

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

and methylazoxymethanol (MAM), the latter of which dissociates into

formaldehyde Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...

and

diazomethane Diazomethane is an organic chemical compound with the formula CH2N2, discovered by German chemist Hans von Pechmann in 1894. It is the simplest diazo compound. In the pure form at room temperature, it is an extremely sensitive explosive yellow ga ...

. It induces

and Zamia staggers, a fatal nervous disease affecting cattle resulting from browsing on the leaves or other parts of cycads.

Sources

Cycasin is found in all known

genera and is distributed throughout the body of the plant, but with the highest concentration in the seeds. It is one of several toxins found in cycad plants, along with the neurotoxic amino acid BMAA. The origin and biological role of these toxins is unknown, as there does not appear to be a statistically significant correlation between the concentration of toxic material and the types of herbivory observed in animals consuming the plants. The enzyme methyl-ONN-azoxymethanol beta-D-glucosyltransferase uses the two substrates

UDP-glucose Uridine diphosphate glucose (uracil-diphosphate glucose, UDP-glucose) is a nucleotide sugar. It is involved in glycosyltransferase reactions in metabolism. Functions UDP-glucose is used in nucleotide sugar metabolism as an activated form of g ...

and methyl-ONN-azoxymethanol to produce UDP and cycasin.

Ecological significance

The butterfly ''

Eumaeus atala ''Eumaeus atala'', also known as the Atala butterfly or coontie hairstreak, is a small colorful butterfly in the family Lycaenidae. It is found in southeastern Florida (including the Florida Keys) in the United States, Cuba, the Bahamas, and the ...

'', whose larvae feed on ''Z. pumila'', contain the poison as a consequence of their diet.

Presence in sago

In order to produce

sago Sago () is a starch extracted from the pith, or spongy core tissue, of various tropical palm stems, especially those of ''Metroxylon sagu''. It is a major staple food for the lowland peoples of New Guinea and the Maluku Islands, where it is c ...

, cycasin and other cycad toxins must be removed from the flesh of the plants. The flesh, seeds, and roots of the cycad are first dried and ground into a fine powder, before being submerged in boiling water. The water is then allowed to drain, leaching out the toxic material while leaving the starch behind. The extracted starch is then alternately dried and pounded until a fine powder is obtained. This repeated pounding and leaching process ensures that there is as little cycasin as possible left behind.

Structure

Cycasin is a

-derived

glycoside In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...

with a methylazoxymethanol substitution at the beta position. Stereochemistry at the azoxy group is (''Z'') (or ''trans'' (''E'') when oxygen removed formally to form azo- group).

Toxicity

Cycasin has an oral of 500 mg/kg. Exposure to cycasin by injection does not cause any permanent ill effects. As a consequence, consumption is not immediately lethal, but will cause a host of liver and neurological problems, as well as causing cancer with long-term exposure. The mechanism of cycasin's toxicity relies on β-glucosidase enzymes found in the gut. Treatment with β-glucosidase causes cycasin to release methylazoxymethanol (MAM), which spontaneously decomposes to form

and

methyldiazonium Methyldiazonium is an organic compound consisting of a methyl group attached to a diazo group. This cation is the conjugate acid of diazomethane, with an estimated p''K''a<10. : Methyldiazonium acidity equilibrium methylating agent. The presence of this molecule methylates DNA, causing long-term damage and potentially giving rise to cancers.

Symptoms

Early symptoms of cycasin poisoning are vomiting, nausea, abdominal pain, and diarrhea. Later stages of poisoning manifest as liver dysfunctions.

Zamia staggers

Livestock that consume raw leaves, nuts, and flour of cycads develop a neurologic syndrome known as zamia staggers, named for the cycad genus ''

Zamia ''Zamia'' is a genus of cycad of the family Zamiaceae, native to North America from the United States (in Georgia and Florida) throughout the West Indies, Central America, and South America as far south as Bolivia. The genus is considered to be ...

'' native to Central and South America. It is clinically characterized by weight loss followed by lateral swaying of the hind quarters, with weakness,

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

, and proprioceptive defects in the rear limbs, and results in demyelination and

axonal An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see spelling differences) is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action pote ...

degeneration in the brain, spinal cord, and

dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dors ...

Suspected association with Lytico-bodig disease

The

Lytico-bodig disease Lytico-Bodig (also Lytigo-bodig) disease, Guam disease, amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), and Western Pacific amyotrophic lateral sclerosis-parkinsonism-dementia complex is a rare, terminal neurodegenerative dis ...

, also known as lateral sclerosis-parkinsonism-dementia, is a

neurodegenerative A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

disease of unknown origin that occurs exclusively in the Chamorro people of the island of

Guam Guam ( ; ) is an island that is an Territories of the United States, organized, unincorporated territory of the United States in the Micronesia subregion of the western Pacific Ocean. Guam's capital is Hagåtña, Guam, Hagåtña, and the most ...

that has characteristics of both

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

(ALS) and

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...

. It is characterized by muscle atrophy, maxillofacial paralysis, inability to speak or swallow, and dementia. The disease is fatal in all cases, with the diaphragm and respiratory accessory muscles becoming paralyzed in the later stages of the disease. Observation of the diets of the native Chamorro people led to the creation of the so-called "Cycad hypothesis." Starches prepared from the seeds of a native cycad species, '' Cycas micronesica'', are used to create the

-like flour ''fadang'', which forms a major part of the diet of the Chamorro people. As the seeds contain the highest amount of the toxin found in the plant, it was proposed that a dietary explanation relating to the consumption of poorly processed fadang was poisoning the natives. After failing to reproduce the symptoms of the disease in animal models, the hypothesis was rejected. Though the initial cycad hypothesis was rejected, a revised form of the hypothesis was proposed by Paul Alan Cox and

Oliver Sacks Oliver Wolf Sacks (9 July 1933 – 30 August 2015) was a British neurology, neurologist, Natural history, naturalist, historian of science, and writer. Born in London, Sacks received his medical degree in 1958 from The Queen's College, Oxford ...

after observing other elements of the Chamorro diet, specifically

flying foxes ''Pteropus'' (suborder Yinpterochiroptera) is a genus of megabats which are among the largest bats in the world. They are commonly known as fruit bats or flying foxes, among other colloquial names. They live in South Asia, Southeast Asia, Austr ...

. The bats accumulate BMAA in their fat by consuming cycad seeds, resulting a in a high concentration of the

neurotoxin Neurotoxins are toxins that are destructive to nervous tissue, nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insult (medical), insultsSpencer 2000 that can adversely affect function ...

References

{{Reflist Glucosides IARC Group 2B carcinogens Cycads