Cycasin

{{Chembox | ImageFile = Cycasin.png | ImageSize = 200px | ImageAlt = Chemical structure of cycasin | ImageClass = skin-invert-image | IUPACName = (''Z'')-1-[(β-D-Glucopyranosyloxy)methyl]-2-methyldiazene 2-oxide | SystematicName = (''Z'')-1-Methyl-2-({[(2''S'',3''R'',4''S'',5''S'',6''R'')-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)diazene 1-oxide | OtherNames = β-D-Glucosyloxyazoxymethane; Methylazoxymethanol β-D-glucoside; Cycas revoluta glucoside; [(''Z'')-Methyl-''ONN''-azoxy]methyl β-D-glucopyranoside<ref>[http://www.chemspider.com/Chemical-Structure.4573631.html b-D-Glucosyloxyazoxymethane], ChemSpider</ref> |Section1={{Chembox Identifiers | CASNo = 14901-08-7 | CASNo_Ref = {{cascite|correct|CAS}} | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 9H51HL0E1D | PubChem = 5459896 | ChemSpiderID = 4573631 | InChI = 1/C8H16N2O7/c1-10(15)9-3-16-8-7(14)6(13)5(12)4(2-11)17-8/h4-8,11-14H,2-3H2,1H3/b10-9-/t4-,5-,6+,7-,8-/m1/s1 | InChIKey = YHLRMABUJXBLCK-LBCXAKKBSA | StdInChI = 1S/C8H16N2O7/c1-10(15)9-3-16-8-7(14)6(13)5(12)4(2-11)17-8/h4-8,11-14H,2-3H2,1H3/b10-9-/t4-,5-,6+,7-,8-/m1/s1 | StdInChIKey = YHLRMABUJXBLCK-LBCXAKKBSA-N | RTECS = | MeSHName = D003492 | ChEBI = 17074 | KEGG = C01418 | SMILES = [O-]/[N+](=N/CO[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)CO)C }} |Section2={{Chembox Properties | C=8 | H=16 | N=2 | O=7 | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = 56.6 g/L<ref>{{Cite web|url=https://foodb.ca/compounds/FDB018287|title=Showing Compound Cycasin (FDB018287) - FooDB}}</ref> }} |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }} '''Cycasin''' is a carcinogenic and neurotoxic glucoside found in cycads such as ''Cycas revoluta'' and ''Zamia pumila''. Symptoms of poisoning include vomiting, diarrhea, weakness, seizures, and hepatotoxicity. In metabolic conditions, cycasin is hydrolyzed into glucose and methylazoxymethanol (MAM), the latter of which dissociates into formaldehyde and diazomethane.<ref name=Laq>{{cite journal|last1=Laqueur|first1=G. L.|last2=Spatz|first2=M.|title=Toxicology of Cycasin|journal=Cancer Research|date=November 1968|volume=28|issue=11|pages=2262–2267|pmid=4881504}}</ref>

It induces hepatotoxicity and Zamia staggers, a fatal nervous disease affecting cattle resulting from browsing on the leaves or other parts of cycads.<ref name=Zam />

==Sources== Cycasin is found in all known cycad 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.<ref>{{cite journal|last1=Moretti|first1=A.|last2=Sabato|first2=S.|last3=Gigliano|first3=G.Siniscalco|title=Taxonomic significance of methylazoxymethanol glycosides in the cycads|journal=Phytochemistry|date=January 1983|volume=22|issue=1|pages=115–117|doi=10.1016/S0031-9422(00)80069-2|bibcode=1983PChem..22..115M }}</ref><ref>{{cite journal|last1=Castillo-Guevara|first1=Citlalli|last2=Rico-Gray|first2=Victor|title=The Role of Macrozamin and Cycasin in Cycads (Cycadales) as Antiherbivore Defenses|journal=Journal of the Torrey Botanical Society|date=July 2003|volume=130|issue=3|pages=206|doi=10.2307/3557555|jstor=3557555}}</ref>

The enzyme methyl-ONN-azoxymethanol beta-D-glucosyltransferase uses the two substrates UDP-glucose and methyl-ONN-azoxymethanol to produce UDP and cycasin.<ref>{{cite journal |vauthors=Tadera K, Yagi F, Arima M, Kobayashi A | year = 1985 | title = Formation of cycasin from methylazoxymethanol by UDP-glucosyltransferase from leaves of Japanese cycad | journal = Agric. Biol. Chem. | volume = 49 | pages = 2827–2828 | doi = 10.1271/bbb1961.49.2827 | issue = 9 | doi-access = free }}</ref>

===Ecological significance=== The butterfly ''Eumaeus atala'', whose larvae feed on ''Z. pumila'', contain the poison as a consequence of their diet.<ref>{{cite journal|last1=Rothschild|first1=Miriam|last2=Nash|first2=Robert J.|last3=Bell|first3=E.Arthur|title=Cycasin in the endangered butterfly Eumaeus atala florida|journal=Phytochemistry|date=July 1986|volume=25|issue=8|pages=1853–1854|doi=10.1016/S0031-9422(00)81161-9|bibcode=1986PChem..25.1853R }}</ref>

===Presence in sago=== In order to produce sago, 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.<ref>{{cite journal|last1=Whiting|first1=Marjorie Grant|title=Toxicity of cycads|journal=Economic Botany|date=October 1963|volume=17|issue=4|pages=270–302|doi=10.1007/BF02860136|s2cid=31799259}}</ref>

==Structure== Cycasin is a glucose-derived glycoside 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).<ref>{{cite journal |last1=Kawaminami |first1=M. |last2=Kawano |first2=I. |last3=Kobayashi |first3=A. |last4=Tadera |first4=K. |last5=Yaki |first5=F. |last6=Kawano |first6=S. |title=The fundamental structure of cycasin, (methyl-ONN-azoxy)methyl β-D-glucopyranoside |journal=Acta Crystallographica Section B: Structural Crystallography and Crystal Chemistry |date=15 November 1981 |volume=37 |issue=11 |pages=2026–2029 |doi=10.1107/S0567740881007887|bibcode=1981AcCrB..37.2026K }}</ref>

==Toxicity== [[File:Methylazoxymethanol.svg|thumb|Methylazoxymethanol (MAM)]] Cycasin has an oral {{LD50}} of 500 mg/kg.<ref>{{cite book|last1=Sax|first1=N Irving|last2=Feiner|first2=Benjamin|title=Dangerous properties of industrial materials|date=1984|publisher=Van Nostrand Reinhold|location=New York|isbn=0442283040|page=828|edition=6th}}</ref> Exposure to cycasin by injection does not cause any permanent ill effects.<ref>{{cite journal|last1=Whiting|first1=Marjorie Grant|title=Toxicity of Cycads|journal=Economic Botany|date=1 January 1963|volume=17|issue=4|pages=270–302|jstor=4252455|doi=10.1007/bf02860136|s2cid=31799259}}</ref> 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 formaldehyde and methyldiazonium. The amount of formaldehyde released is too small to induce toxicity, but methyldiazonium is a potent methylating agent. The presence of this molecule methylates DNA, causing long-term damage and potentially giving rise to cancers.<ref name=Laq />

===Symptoms=== Early symptoms of cycasin poisoning are vomiting, nausea, abdominal pain, and diarrhea. Later stages of poisoning manifest as liver dysfunctions. <ref>{{cite web|title=Symptoms of Plant toxin-induced liver damage -- Cycasin - RightDiagnosis.com|url=http://www.rightdiagnosis.com/p/plant_toxin_induced_liver_damage_cycasin/symptoms.htm|website=www.rightdiagnosis.com|publisher=Healthgrades}}</ref>

===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'' native to Central and South America. It is clinically characterized by weight loss followed by lateral swaying of the hind quarters, with weakness, ataxia, and proprioceptive defects in the rear limbs, and results in demyelination and axonal degeneration in the brain, spinal cord, and dorsal root ganglia.<ref name=Zam>{{cite journal|last1=Reams|first1=Rachel Y.|last2=Janovitz|first2=Evan B.|last3=Robinson|first3=Farrel R.|last4=Sullivan|first4=John M.|last5=Casanova|first5=Carlos Rivera|last6=Más|first6=Edwin|title=Cycad Toxicosis in a Group of Dairy Heifers in Puerto Rico|journal=Journal of Veterinary Diagnostic Investigation|date=July 1993|volume=5|issue=3|pages=488–494|doi=10.1177/104063879300500337|pmid=8373871|doi-access=free}}</ref>

===Suspected association with Lytico-bodig disease=== The Lytico-bodig disease, also known as lateral sclerosis-parkinsonism-dementia, is a neurodegenerative disease of unknown origin that occurs exclusively in the Chamorro people of the island of Guam that has characteristics of both amyotrophic lateral sclerosis (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.<ref name=Bradley>{{cite journal|last1=Bradley|first1=Walter G.|last2=Mash|first2=Deborah C.|title=Beyond Guam: The cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases|journal=Amyotrophic Lateral Sclerosis|date=25 November 2009|volume=10|issue=sup2|pages=7–20|doi=10.3109/17482960903286009|pmid=19929726|s2cid=41622254}}</ref>

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 sago-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.<ref name=Bradley /> Though the initial cycad hypothesis was rejected, a revised form of the hypothesis was proposed by Paul Alan Cox and Oliver Sacks after observing other elements of the Chamorro diet, specifically flying foxes. The bats accumulate BMAA in their fat by consuming cycad seeds, resulting a in a high concentration of the neurotoxin.<ref name = "Cox1">{{cite journal |vauthors=Cox PA, Banack SA, Murch SJ |year = 2003 |title = Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam |journal = PNAS |volume = 100 |issue = 23 |pages = 13380–13383 |doi=10.1073/pnas.2235808100| bibcode = 2003PNAS..10013380C|pmc = 263822 |pmid=14612559|doi-access = free }}</ref> [[File:Cycas micronesica photo courtesy A. Gawel (15391498081).jpg|thumb|''Cycas micronesica'', one of the cycad species consumed by the Chamorro]]

== References == {{Reflist}}

Category:Glucosides Category:IARC Group 2B carcinogens Category:Cycads