Цикутоксин: синтез, механизм действия и токсикологические свойства

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).

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.

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

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.

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). 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. 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. 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.

Cicutoxin has been shown to have anti leukemia properties as it inhibits the proliferation of the lymphocytes. 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.