Cicutoxin

Cicutoxin is a naturally-occurring poisonous chemical compound produced by several plants from the Apiaceae family including water hemlock (Cicuta species) and water dropwort (Oenanthe crocata). The compound contains polyene, polyyne, and alcohol functional groups and is a structural isomer of oenanthotoxin, also found in water dropwort. Both of these belong to the C17-polyacetylenes chemical class.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 Cicuta virosa plant, and he also extracted and named the isomeric toxin oenanthotoxin from Oenanthe crocata. A review published in 1911 examined 27 cases of cicutoxin poisoning, 21 of which had resulted in death – 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 review from 1962 examined 78 cases, 33 of which resulted in death, and cases of cicutoxin poisoning continue to occur:Cicutoxin is found in five species of water hemlock, all belonging to the Apiaceae family. These include all four species in the Cicuta genera and one species from the Oenanthe genera: 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 C17 polyactylenes. 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 such as Virol A and Virol C.Building on Boehm's work, Jacobsen reported the first isolation of pure cicutoxin as a yellowish oil in 1915. Its chemical structure was not determined until 1953, however, when it was shown that it has a molecular formula of C17H22O2 and it is an aliphatic, highly unsaturated alcohol with two triple bonds conjugated with three double bonds, and two hydroxyl groups. The first synthesis of cicutoxin was reported in 1955. 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.' 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. Outside of a plant, cicutoxin breaks down when exposed to air, light, or heat, making it difficult to handle.Cicutoxin is known to interact with the GABAA receptor and it also has been shown to block the potassium channel in T lymphocytes. A similar effect where potassium channels in neurons are blocked could account for the toxic effect on the nervous system. The interactions are explained in Mechanism of action.First signs of cicutoxin poisoning start 15–60 minutes after ingestion and are vomiting, convulsions, widened pupils, salivation, excess sweating and the patient may go into a coma. Other described symptoms are cyanosis, amnesia, absence of muscle reflexes, metabolic acidosis and cardiovascular changes which may cause heart problems and central nervous system problems which manifest themselves as convulsions and either an overactive or underactive heart. Due to an overactive nervous system respiratory failure occurs which may cause 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.Cicutoxin has been shown to have anti-leukemia properties as it inhibits the proliferation of the lymphocytees. 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. Cicutoxin is also used as a natural drug against breast cancer, because of its antitumor activity.