Cicutoxin

Source: Wikipedia, the free encyclopedia.
Not to be confused with Ciguatoxin.
Cicutoxin
Names
Preferred IUPAC name
(8E,10E,12E,14R)-Heptadeca-8,10,12-triene-4,6-diyne-1,14-diol
Other names
Cicutoxin
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
KEGG
UNII
  • InChI=1S/C17H22O2/c1-2-14-17(19)15-12-10-8-6-4-3-5-7-9-11-13-16-18/h4,6,8,10,12,15,17-19H,2,11,13-14,16H2,1H3/b6-4+,10-8+,15-12+/t17-/m1/s1
    Key: FQVNSJQTSOVRKZ-JNRDBWBESA-N
  • CCC[C@@H](O)\C=C\C=C\C=C\C#CC#CCCCO
Properties
C17H22O2
Molar mass 258.361 g·mol−1
Density 1.025 g/mL
Melting point 54 °C (129 °F; 327 K) (single enantiomer); 67 °C (racemic mixture)
Boiling point 467.2 °C (873.0 °F; 740.3 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Cicutoxin is a

chemical class.[2]

It causes death by

seizures, and death.[1] LD50(mouse; i.p.) ~9 mg/kg[3]

History

itching, resulting in the deaths of two children, a report that suggests that cicutoxin may be absorbed through the skin.[7][5] A review from 1962 examined 78 cases, 33 of which resulted in death,[1] and cases of cicutoxin poisoning continue to occur:[9]

All plants from the genus Cicuta contain cicutoxin. These plants are found in swampy, wet habitats in North America and parts of Europe. The Cicuta plants are often mistaken for edible roots such as parsnip, wild carrot or wild ginseng.[10] All parts of the Cicuta plants are poisonous, though the root is the most toxic part of the plant[1] and toxin levels are highest in spring[8] – ingestion of a 2–3 cm portion of root can be fatal to adults.[10][13] In one reported incident, 17 boys ingested parts of the plant, with only those who consumed the root experiencing seizures whilst those who consumed only leaves and flowers merely became unwell. The toxicity of the plants depends on various factors, such as seasonal variation, temperature, geographical location and soil conditions. The roots remain toxic even after drying.[8]

Plants containing cicutoxin

Cicuta virosa, Mackenzie's water hemlock

Cicutoxin is found in five species of water hemlock, all belonging to the

geometric isomer of cicutoxin, while O. crocata contains the toxin oenanthotoxin, a structural isomer of cicutoxin. Cicuta plants also produce multiple congeners of cicutoxin, such as Virol A and Virol C.[2]

Chemistry

Building on Boehm's work,

hydroxyl groups.[18] The first synthesis of cicutoxin was reported in 1955.[19] Though the overall yield was only 4% and the product was the racemic mixture, the synthesis has been described as "a significant accomplishment" given that it was achieved "without the benefit of modern coupling reactions."[2] The absolute configuration of the naturally-occurring form of cicutoxin was reported in 1999 to be (R)-(−)-cicutoxin, systematically named as (8E,10E,12E,14R)-heptadeca-8,10,12-triene-4,6-diyne-1,14-diol.[20] Outside of a plant, cicutoxin breaks down when exposed to air, light, or heat, making it difficult to handle.[17]

Cicutoxin has a long carbon structure and few hydrophilic substituents which gives it hydrophobic characteristics. Hydrophobic and/or small molecules can be absorbed through the skin. Research has shown that cicutoxin will pass through the skin of frogs[21] and the experience of the family who used a Cicuta plant as a topical antipruritic[7] strongly suggests that the compound is able to pass through human skin.[5]

Laboratory synthesis

The first

Corey-Bakshi-Shibata reduction of 1-hexyn-3-one. 1,4-diiodo-1,3-butadiene (9) is also a known compound and it is readily available by dimerization of acetylene accompanied by addition of iodine in the presence of platinum (IV) catalyst and sodium iodide. The last key fragment, THP
-protected 4,6-heptadiyn-1-ol (6) is a known compound.

The first step is the

Red-Al. The last step is the removal of the THP protection group. When THP is removed and a hydrogen is bound to the oxygen, then (R)-(–)-cicutoxin is formed. These four steps are the full synthesis of cicutoxin and gives an overall yield of 18 percent.[2]

Biochemistry

Cicutoxin is known to interact with the

T lymphocytes. A similar effect where potassium channels in neurons are blocked could account for the toxic effect on the nervous system.[22]
The interactions are explained in Mechanism of action.

Mechanism of action

The exact mechanism of action is not known for cicutoxin, even though it is well known to be a violent toxin. The mechanism is not known because of the chemical instability of cicutoxin,[23] but there have been studies that delivered some evidence for a mechanism of action.

Cicutoxin is a noncompetitive gamma-aminobutyric acid (

seizures.[24]

There also have been some studies that suggest that cicutoxin increases the duration of the neuronal repolarization in a dose-dependent manner. The toxin could increase the duration of the repolarization up to sixfold at 100 µmol L−1. The prolonged action potentials may cause higher excitatory activity.[24]

It has been demonstrated that cicutoxin also blocks

T-lymphocytes.[25] The toxin inhibits the proliferation of the lymphocytes . This has made it a substance of interest in research for a medicine against leukemia
.

Metabolism

It is unknown how the body gets rid of cicutoxin. There is evidence that it has a long half-life in the body[citation needed], because of a patient who was submitted in a hospital after eating a root of a Cicuta plant. The man was in the hospital for two days and still had a fuzzy feeling in his head two days after leaving the hospital.[21] There is also the case of a sheep (discussed in Effects on animals) where the sheep fully recovered after seven days.[24]

Poisoning

Symptoms

First signs of cicutoxin poisoning start 15–60 minutes after ingestion and are

suffocation and accounts for most of the deaths. Dehydration from water loss due to vomiting can also occur. If untreated, the kidneys can also fail, causing death.[18]

Treatment

The adverse effects from cicutoxin poisoning are

barbiturates to reduce seizures.[1]

Effects on animals

The

LD50 of cicutoxin for mice is 2.8 mg kg−1 (10.8 μmol kg−1). In comparison, the LD50 of virol A is 28.0 mg kg−1 (109 μmol kg−1) and of isocicutoxin is 38.5 mg kg−1 (149 μmol kg−1).[20]

Cattle usually ingest parts of Cicuta plants in Spring, while grazing on new growth around ditches and rivers where these plants grow. Animals display similar effects of cicutoxin poisoning as do humans, but without vomiting (which can lead to increased lethality) – recorded symptoms include salivation, seizures, frequent urination and

tubers, taking up to seven days to recover fully.[24]

Research studies on ewes has shown that skeletal and cardiac myodegeneration (damage of muscle tissues) only occur after a dose sufficient to induce symptoms of intoxication is administered. Analysis of the animal's blood showed elevated serum enzymes that indicate muscle damage (

lesions. The number and duration of seizures had a direct effect on the skeletal and cardiac myodegeneration and amount of serum change.[24]

Ewes given up to 2.5 times the lethal dose along with medications to treat symptoms of cicutoxin poisoning recovered, demonstrating that symptomatic treatment can be life-saving. Medications administered included

salivary excretion during anesthesia, and Ringer's lactate solution until the ewes recovered.[24]

Medical use

Cicutoxin has been shown to have anti-leukemia properties[17] as it inhibits the proliferation of the lymphocytes.[25] It has also been investigated for antitumor activity, where it was shown that a methanolic extract of C. maculata demonstrated significant cytotoxicity in the 9 KB (human nasopharyngeal carcinoma) cell structure assay.[17]

References

  1. ^
    S2CID 21855822
    .
  2. ^
    PMID 24273444
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  3. ISBN 9780881929522
    .
  4. ^ Wepfer, Johann Jakob (1679). Cicutae Aquaticae Historia Et Noxae Commentario Illustrata (in Latin).
  5. ^
    ISBN 9780471727613
    .
  6. ^
    S2CID 335727
    .
  7. ^
    doi:10.1001/archinte.1911.00060030061002
    .
  8. ^
    PMID 6664385
    .
  9. United States National Institutes of Health
    . December 20, 2006. Retrieved July 21, 2018.
  10. ^
    PMID 8145712
    .
  11. ISBN 9780071360012
    .
  12. PMID 11205076
    .
  13. ^ Kingsbury, J. M. (1964). Poisonous Plants of the United States and Canada. Englewood Cliffs, New Jersey: Prentice Hall. p. 372.
  14. ISBN 9781482250640
    .
  15. doi:10.1139/b80-204
    .
  16. doi:10.1021/ja02169a021
    .
  17. ^
    PMID 3572419
    .
  18. ^
    doi:10.1039/JR9530000309
    .
  19. ^
    doi:10.1039/JR9550001770
    .
  20. ^
    doi:10.1016/S0040-4020(99)00706-1
    .
  21. ^
    PMID 4013278
    .
  22. ^
    ISBN 9780071347211
    .
  23. ^
    PMID 11087575
    .
  24. ^
    PMID 8953535
    .
  25. ^
    PMID 8604987
    .
  26. ISBN 9780080472072
    .
  27. PMID 16376150
    .

Additional References
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