Cycasin is a

carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive sub ...

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 found in

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

s such as '' Cycas revoluta'' and '' Zamia pumila''. Symptoms of poisoning include vomiting, diarrhea, weakness, seizures, and

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cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

. In metabolic conditions, cycasin is hydrolyzed into glucose and methylazoxymethanol (MAM), the latter of which dissociates into

formaldehyde Formaldehyde ( , ) ( systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...

and

diazomethane Diazomethane is the chemical compound 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 gas; thus, it is almos ...

. 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 β-Methylamino--alanine, or BMAA, is a non-proteinogenic amino acid produced by cyanobacteria. BMAA is a neurotoxin and its potential role in various neurodegenerative disorders is the subject of scientific research. Structure and properties ...

. 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'', 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 ...

, 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 insures that there is as little cycasin as possible left behind.

Structure

Cycasin is a

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, usi ...

-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 glycoside ...

with a

methylazoxymethanol Methylazoxymethanol, MAM, is a carcinogen which reduces DNA synthesis. Its derivatives include methylazoxymethanol acetate Methylazoxymethanol acetate, MAM, is a neurotoxin which reduces DNA synthesis used in making animal models of neurologic ...

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

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...

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 β-Glucosidase (EC 3.2.1.21; systematic name β-D-glucoside glucohydrolase) is an enzyme that catalyses the following reaction: : Hydrolysis of terminal, non-reducing β-D-glucosyl residues with release of β-D-glucose Structure β-Glucosidas ...

enzymes found in the gut. Treatment with β-glucosidase causes cycasin to release

(MAM), which spontaneously decomposes to form

and methyl-diazonium. The amount of formaldehyde released is too small to induce toxicity, but methyl-diazonium is a potent methylating agent. The presence of this molecule methylates DNA, causing long-term damage and potentially giving rise to cancers. Methylazoxymethanol

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 is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of t ...

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

demyelination A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...

and axonal degeneration in the brain, spinal cord, and dorsal root ganglia.

Suspected association with Lytico-bodig disease

The

Lytico-bodig disease Lytico-bodig (also Lytigo-bodig) disease, Guam disease, or amyotrophic lateral sclerosis-parkinsonism-dementia (ALS-PDC) is a Neurodegeneration, neurodegenerative disease of uncertain etiology endemic to the Chamorro people of the island of Guam in ...

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

neurodegenerative A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

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

Guam Guam (; ch, Guåhan ) is an organized, unincorporated territory of the United States in the Micronesia subregion of the western Pacific Ocean. It is the westernmost point and territory of the United States (reckoned from the geographic ce ...

that has characteristics of both

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

(ALS) and parkinsonism. 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 neurologist, naturalist, historian of science, and writer. Born in Britain, Sacks received his medical degree in 1958 from The Queen's College, Oxford, before moving to the Uni ...

after observing other elements of the Chamorro diet, specifically flying foxes. The bats accumulate

in their fat by consuming cycad seeds, resulting a in a high concentration of the neurotoxin. Cycas micronesica photo courtesy A

References

{{Reflist Glucosides IARC Group 2B carcinogens