Cicutoxin is a naturally-occurring poisonous chemical compound produced by several plants from the family Apiaceae including water hemlock (Cicuta species) and water dropwort (Oenanthe crocata). All of these belong to the C<sub>17</sub>-polyacetylenes chemical class.

History

Johann Jakob Wepfer's book Cicutae Aquaticae Historia Et Noxae Commentario Illustrata was published in 1679; it contains the earliest published report of toxicity associated with Cicuta plants. The name cicutoxin was coined by Boehm in 1876 for the toxic compound arising from the plant Cicuta virosa, and he also extracted and named the isomeric toxin oenanthotoxin from Oenanthe crocata. &ndash; though some of these cases involved deliberate poisoning. This review included a case where a family of five used Cicuta extracts as a topical treatment for itching, resulting in the deaths of two children, a report that suggests that cicutoxin may be absorbed through the skin.

  • A child used the stem of a plant as a toy whistle and died of cicutoxin poisoning
  • A 14-year-old boy died 20 hours after consuming a 'wild carrot' in 2001
  • In 1992, two brothers were foraging for wild ginseng and found a hemlock root. One of them ate three bites of the supposed ginseng root and the other one ingested one bite. The first brother died three hours later while the second made a full recovery with supportive medical care after experiencing seizures and delirium.

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. 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. and one species from the genus Oenanthe: the bulblet-bearing water hemlock, C. bulbifera; the Douglas water hemlock, C. douglasii; the spotted water hemlock or spotted cowbane, C. maculata; Mackenzie's water hemlock, C. virosa; and, the water dropwort, O. crocata. Cicutoxin is found in all parts of these plants, along with several other C<sub>17</sub> polyacetylenes. C. virosa, for example, produces isocicutoxin, a 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.

<!-- comment out for now: All of these plants contain a similar toxin. The principal structure of these toxins is a C17 conjugated polyacetylene with a terminal hydroxyl group and an allylic hydroxyl group attached at C14. These toxins can be extracted from the plants named above or they can be synthesized.

The family Apiaceae contains numerous other genera with edible plants and confusion between edible and poisonous plants has resulted in cases of accidental poisoning. -->

Chemistry

Building on Boehm's work, The first synthesis of cicutoxin was reported in 1955. Outside of a plant, cicutoxin breaks down when exposed to air, light, or heat, making it difficult to handle.

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 and the experience of the family who used a Cicuta plant as a topical antipruritic A complete synthesis of the natural product, (R)-(−)-cicutoxin, in four linear steps was reported in 1999, from three key fragments: (R)-(−)-1-hexyn-3-ol (8), 1,4-diiodo-1,3-butadiene (9), and THP-protected 4,6-heptadiyn-1-ol (6). 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, but there have been studies that delivered some evidence for a mechanism of action.

Cicutoxin is a noncompetitive gamma-aminobutyric acid (GABA) antagonist in the central nervous system (CNS). GABA normally binds to the beta domain of the GABA<sub>A</sub> receptor and activates the receptor which causes a flow of chloride across the membrane. Cicutoxin binds to the same place as GABA, because of this the receptor is not activated by GABA. The pore of the receptor won't open and chloride can't flow across the membrane. Binding of cicutoxin to the beta domain also blocks the chloride channel. Both effects of cicutoxin on the GABA<sub>A</sub>-receptor cause a constant depolarization. This causes hyperactivity in cells, which leads to seizures.

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&nbsp;μmol/L. The prolonged action potentials may cause higher excitatory activity. 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, 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. or barbiturates to reduce seizures.