Cicutoxin

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Cicutoxin
Cicutoxin.svg
Cicutoxin 3d structure.png
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
PubChem CID
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 naturally-occurring poisonous chemical compound produced by several plants from the family Apiaceae including water hemlock ( Cicuta species) and water dropwort ( Oenanthe crocata ). [1] 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. [2]

Contents

It causes death by respiratory paralysis resulting from disruption of the central nervous system. [2] It is a potent, noncompetitive antagonist of the gamma-aminobutyric acid (GABA) receptor. In humans, cicutoxin rapidly produces symptoms of nausea, emesis and abdominal pain, typically within 60 minutes of ingestion. This can lead to tremors, seizures, and death. [1] LD50(mouse; i.p.) ~9 mg/kg [3]

History

Johann Jakob Wepfer's book Cicutae Aquaticae Historia Et Noxae Commentario Illustrata was published in 1679; [4] it contains the earliest published report of toxicity associated with Cicuta plants. [5] The name cicutoxin was coined by Boehm in 1876 for the toxic compound arising from the plant Cicuta virosa , [6] and he also extracted and named the isomeric toxin oenanthotoxin from Oenanthe crocata . [5] A review published in 1911 examined 27 cases of cicutoxin poisoning, 21 of which had resulted in death [7] – though some of these cases involved deliberate poisoning. [8] 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. [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 Cicuta virosa - Kohler-s Medizinal-Pflanzen-038 cropped.jpg
Cicuta virosa , Mackenzie's water hemlock

Cicutoxin is found in five species of water hemlock, all belonging to the family Apiaceae. These include all four species in the genus Cicuta [14] 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 ; [15] and, the water dropwort, O. crocata . [1] Cicutoxin is found in all parts of these plants, along with several other C17 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. [2]

Chemistry

Building on Boehm's work, [6] Jacobsen reported the first isolation of pure cicutoxin as a yellowish oil in 1915. [16] [17] 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. [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 total synthesis of racemic cicutoxin was published in 1955 and reported that this racemate was about twice as active as the naturally-occurring enantiomer. [19] 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). [2] (R)-(–)-1-hexyn-3-ol (8) is a known compound and was obtained by 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 Sonogashira coupling of compound 8 and 9. This step gave dienynol (10) with 63 percent yield. The second step is a palladium -catalyzed coupling reaction. The coupling of compound 6 and 10 leads to the 17-carbon frame (11) with 74 percent yield. Compound 11 already has the stereo center in place and only needs a few structural changes: the third and fourth step. The third step is the reduction of the C5 triple bond in compound 11, this was accomplished by using a compound called 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 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. [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 (GABA) antagonist in the central nervous system (CNS). GABA normally binds to the beta domain of the GABAA 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 GABAA-receptor cause a constant depolarization. This causes hyperactivity in cells, which leads to 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. The prolonged action potentials may cause higher excitatory activity. [24]

It has been demonstrated that cicutoxin also blocks potassium channels in 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: vomiting, convulsions, widened pupils, salivation, excess sweating. It may cause 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. [22] [23] [25] 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. [18]

Treatment

The adverse effects from cicutoxin poisoning are gastrointestinal or cardiac nature. With no antidote known, only symptomatic treatments are available, though supportive treatments do substantially improve survival rates. [18] Treatments used include the administration of activated charcoal within 30 minutes of ingestion to reduce the uptake of poison, maintaining open airways to prevent suffocation, rehydration to address the dehydration caused by vomiting, and administration of benzodiazepines that enhance the effect of GABA on the GABAA receptor [26] [27] or barbiturates to reduce seizures. [1]

Effects on animals

The LD50 of cicutoxin for mice is 2.8 mg/kg (10.8 μmol/kg). In comparison, the LD50 of virol A is 28.0 mg/kg (109 μmol/kg) and of isocicutoxin is 38.5 mg/kg (149 μmol/kg). [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 defecation, and degeneration of skeletal and cardiac muscles. Seizures are usually short, less than a minute per seizure, and occur at intervals of 15 to 30 minutes for around two hours. Ewes recover more slowly after eating cicutoxin-containing 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 (LDH, AST and CK values). At necropsy, the ewe's heart had multifocal pale areas and pallor of the long digital extensor muscle groups; by contrast, a ewe given a lethal dose of cicutoxin-containing tubers had only microscopic 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 sodium pentobarbital (at 20–77 mg/kg intravenously) at the first seizure to control seizure activity, atropine (75–150 mg) to reduce 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]

Related Research Articles

<span class="mw-page-title-main">Poison</span> Substance that causes death, injury or harm to organs

A poison is any child chemical substance that is harmful or lethal to living organisms. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figuratively, with a broad sense.

<i>Oenanthe</i> (plant) Genus of flowering plants in the umbellifer family Apiaceae

Oenanthe, known as water dropworts, oenanthes, water parsleys, and water celeries, are a genus of plants in the family Apiaceae. Most of the species grow in damp ground, such as in marshes or in water.

<i>Conium</i> Genus of flowering plants in the celery family Apiaceae

Conium is a genus of flowering plants in the family Apiaceae. As of December 2020, Plants of the World Online accepts six species.

Gyromitrin is a toxin and carcinogen present in several members of the fungal genus Gyromitra, like G. esculenta. Its formula is C4H8N2O. It is unstable and is easily hydrolyzed to the toxic compound monomethylhydrazine CH3NHNH2. Monomethylhydrazine acts on the central nervous system and interferes with the normal use and function of vitamin B6. Poisoning results in nausea, stomach cramps, and diarrhea, while severe poisoning can result in convulsions, jaundice, or even coma or death. Exposure to monomethylhydrazine has been shown to be carcinogenic in small mammals.

<i>Cicuta virosa</i> Species of plant

Cicuta virosa, the cowbane or northern water hemlock, is a poisonous species of Cicuta, native to northern and central Europe, northern Asia and northwestern North America.

<i>Amanita virosa</i> Species of fungus

Amanita virosa is a species of fungus in the class Agaricomycetes. In the UK, it has the recommended English name of destroying angel and is known internationally as the European destroying angel. Basidiocarps are agaricoid (mushroom-shaped) and pure white with a ring on the stem and a sack-like volva at the base. The species is deadly poisonous. It occurs in Europe and northern Asia. Amanita virosa was formerly reported from North America, but research has shown that similar-looking American species, including Amanita bisporigera and A. ocreata, are distinct.

<span class="mw-page-title-main">Muscimol</span> Neurotransmission inhibitor

Muscimol is one of the principal psychoactive constituents of Amanita muscaria and related species of mushroom. Muscimol is a potent and selective orthosteric agonist for the GABAA receptor and displays sedative-hypnotic, depressant and hallucinogenic psychoactivity. This colorless or white solid is classified as an isoxazole.

<span class="mw-page-title-main">Picrotoxin</span> Chemical compound

Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812. The name "picrotoxin" is a combination of the Greek words "picros" (bitter) and "toxicon" (poison). A mixture of two different compounds, picrotoxin occurs naturally in the fruit of the Anamirta cocculus plant, although it can also be synthesized chemically.

<i>Cicuta douglasii</i> Species of flowering plant

Cicuta douglasii, the western water hemlock, is a very poisonous perennial plant in the family Apiaceae.

<i>Cicuta</i> Genus of plants

Cicuta, commonly known as water hemlock, is a genus of four species of highly poisonous plants in the family Apiaceae. They are perennial herbaceous plants which grow up to 2.5 meters (8 ft) tall, having distinctive small green or white flowers arranged in an umbrella shape (umbel). Plants in this genus may also be referred to as cowbane or poison parsnip. Cicuta is native to temperate regions of the Northern Hemisphere, mainly North America and Europe, typically growing in wet meadows, along streambanks and other wet and marshy areas. These plants bear a close resemblance to other members in the family Apiaceae and may be confused with a number of edible or poisonous plants. The common name hemlock may also be confused with poison hemlock, or with the Hemlock tree.

<i>Cicuta maculata</i> Species of plant

Cicuta maculata is a highly poisonous species of flowering plant in the carrot family known by several common names, including spotted water hemlock, spotted parsley, and spotted cowbane. It is native to nearly all of North America, from northern Canada to southern Mexico.

<span class="mw-page-title-main">Tetramethylenedisulfotetramine</span> Chemical compound

Tetramethylenedisulfotetramine (TETS) is an organic compound used as a rodenticide. It is an odorless, tasteless white powder that is slightly soluble in water, DMSO and acetone, and insoluble in methanol and ethanol. It is a sulfamide derivative. It can be synthesized by reacting sulfamide with formaldehyde solution in acidified water. When crystallized from acetone, it forms cubic crystals with a melting point of 255–260 °C.

<span class="mw-page-title-main">Oenanthotoxin</span> Chemical compound

Oenanthotoxin is a toxin extracted from hemlock water-dropwort and other plants of the genus Oenanthe. It is a central nervous system poison, and acts as a noncompetitive antagonist of the neurotransmitter gamma-aminobutyric acid. A case has been made for the presence of this toxin in local Oenanthe species playing a causative role in euthanasia in ancient Sardinia. It was crystallized in 1949 by Clarke and co-workers. It is structurally closely related to the toxins cicutoxin and carotatoxin. Oenanthotoxin is a C17 polyacetylene isomer of cicutoxin.

<span class="mw-page-title-main">Anisatin</span> Chemical compound

Anisatin is an extremely toxic, insecticidally active component of the shikimi plant. The lethal dose is 1 mg/kg (i.p.) in mice. Symptoms begin to appear about 1–6 hours after ingestion, beginning with gastrointestinal ailments, such as diarrhea, vomiting, and stomach pain, followed by nervous system excitation, seizures, loss of consciousness, and respiratory paralysis, which is the ultimate cause of death.

A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent excitotoxicity. Most convulsants are antagonists at either the GABAA or glycine receptors, or ionotropic glutamate receptor agonists. Many other drugs may cause convulsions as a side effect at high doses but only drugs whose primary action is to cause convulsions are known as convulsants. Nerve agents such as sarin, which were developed as chemical weapons, produce convulsions as a major part of their toxidrome, but also produce a number of other effects in the body and are usually classified separately. Dieldrin which was developed as an insecticide blocks chloride influx into the neurons causing hyperexcitability of the CNS and convulsions. The Irwin observation test and other studies that record clinical signs are used to test the potential for a drug to induce convulsions. Camphor, and other terpenes given to children with colds can act as convulsants in children who have had febrile seizures.

<span class="mw-page-title-main">Tutin (toxin)</span> Chemical compound

Tutin is a poisonous plant derivative found in New Zealand tutu plants. It acts as a potent antagonist of the glycine receptor, and has powerful convulsant effects. It is used in scientific research into the glycine receptor. It is sometimes associated with outbreaks of toxic honey poisoning when bees feed on honeydew exudate from the sap-sucking passion vine hopper insect, when the vine hoppers have been feeding on the sap of tutu bushes. Toxic honey is a rare event and is more likely to occur when comb honey is eaten directly from a hive that has been harvesting honeydew from passionvine hoppers feeding on tutu plants.

<i>Conium maculatum</i> Poisonous herbaceous plant in the carrot family

Conium maculatum, known as hemlock, or poison hemlock is a highly poisonous flowering plant in the carrot family Apiaceae, native to Europe and North Africa. It is herbaceous without woody parts and has a biennial lifecycle. A hardy plant capable of living in a variety of environments, hemlock is widely naturalised in locations outside its native range, such as parts of Australia, West Asia, and North and South America, to which it has been introduced. It is capable of spreading and thereby becoming an invasive weed.

<span class="mw-page-title-main">Toxalbumin</span> Toxic plant proteins

Toxalbumins are toxic plant proteins that disable ribosomes and thereby inhibit protein synthesis, producing severe cytotoxic effects in multiple organ systems. They are dimers held together by a disulfide bond and comprise a lectin part which binds to the cell membrane and enables the toxin part to gain access to the cell contents. Toxalbumins are similar in structure to AB toxins found in cholera, tetanus, diphtheria, botulinum and others; and their physiological and toxic properties are similar to those of viperine snake venom.

<i>Cicuta bulbifera</i> Species of plant

Cicuta bulbifera, commonly known as the bulb-bearing water-hemlock, is a plant native to North America and one of four species in the poisonous genus Cicuta. Tiny bulbils form in the leaf joints in the upper part of the plant, giving the plant its scientific and common names. Cicuta bulbifera can be distinguished from Cicuta douglasii by its narrow leaflet segments and its bulbil-bearing upper leaf axils.

<i>Oenanthe crocata</i> Species of flowering plant

Oenanthe crocata, hemlock water-dropwort is a flowering plant in the carrot family, native to Europe, North Africa and western Asia. It grows in damp grassland and wet woodland, often along river and stream banks. All parts of the plant are extremely toxic and it has been known to cause human and livestock poisoning.

References

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  26. ↑ Olsen, Richard W.; Betz, Heinrich (2005). "GABA and Glycine". In Siegel, George J.; Albers, R. Wayne; Brady, Scott T.; Price, Donald L. (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (7th ed.). Elsevier. pp. 291–302. ISBN   9780080472072.
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