Fabrizio Viberti, Elisa Raveggi 03/04/2014
Aconitine is a toxin produced by the Aconitum plant.
Aconitum (also known as "the queen of poisons", aconite, monkshood, wolf's bane, leopard's bane, women's bane, devil's helmet or blue rocket) is a genus of over 250 species of flowering plants belonging to the family Ranunculaceae. These herbaceous perennial plants are chiefly native to the mountainous parts of the northern hemisphere, growing in the moisture-retentive but well-draining soils of mountain meadows. Most species are extremely poisonous and must be handled carefully.
Aconitine, also known as acetylbenzoylaconitane, is a C19 norditerpenoid alkaloid. Its molecular formula is C34H47NO112. It has 3 hydrogen bond donors, 12 hydrogen bond acceptors, 7.7 flexible bonds.
Aconitine belongs to the family of aconitum alkaloids and is barely soluble in water, but very soluble in organic solvents such as chloroform or diethyl ether. Aconitine is also soluble in mixtures of alcohol and water if the concentration of alcohol is high enough.
Aconitine is synthesized by the aconitum plant via terpenoid biosynthesis from methylerythritol phosphate pathway that polymerizes subsequent to phosphorylation.
MECHANISM OF ACTION
Aconitine interacts with the voltage-gated sodium ion channels.
Sodium ion channels are heteromeric glycoproteins bound in the membrane of cells in excitable tissue, such as muscles and neurons. They are highly selective for sodium ions, open rapidly to depolarize the membrane, and close to repolarize the membrane. Their conformation changes are essential for the generation of the action potential. When open, they permit ions to flow across the plasma membrane through their pores.
In the muscles, aconitine potentiates contractions. It increases the permeability of the smooth muscle membrane to sodium ions, increasing calcium ion availability and, therefore, muscular contraction.
In the neurons, aconitine depolarizes both the presynaptic and postsynaptic membranes by opening voltage-gated sodium ion channels. This change in voltage across the membrane leads to a higher concentration of calcium ions in the presynaptic axon terminal by opening voltage-gated calcium ion channels. The influx of calcium ions can stimulate or enhance neurotransmitter release. Both excitatory and inhibitory neurotransmitters may be released and involved in the activity of aconitine on the postsynaptic cell, in addition to its direct action on the postsynaptic voltage-gated sodium ion channels.
Aconitine is metabolized by the cytochrome p450 isoenzymes, mainly by CYP3A4, 3A5 and 2D6. CYP2C8 and 2C9 had a minor role to the aconitine metabolism.
The cardiotoxicity and neurotoxicity of aconitine and related alkaloids are due to their actions on the voltage-sensitive sodium channels of the cell membranes of excitable tissues, including the myocardium, nerves, and muscles. As previously said, aconitine binds with high affinity to the open state of the voltage-sensitive sodium channels at site 2, thereby causing a persistent activation of the sodium channels, which become refractory to excitation. The electrophysiological mechanism of arrhythmia induction is triggered activity due to delayed after-depolarization and early after-depolarization. The arrhythmogenic properties of aconitine are in part due to its cholinolytic (anticholinergic) effects mediated by the vagus nerve. Aconitine has a positive inotropic effect by prolonging sodium influx during the action potential. It has hypotensive and bradycardic actions due to activation of the ventromedial nucleus of the hypothalamus. Through its action on voltage-sensitive sodium channels in the axons, aconitine blocks neuromuscular transmission by decreasing the evoked quantal release of acetylcholine. Aconitine, can induce strong contractions of the ileum through acetylcholine release from the postganglionic cholinergic nerves.
Marked symptoms appear within a few minutes of the administration of a poisonous dose of aconite. The initial signs are gastrointestinal. There is a sensation of burning, tingling, and numbness in the mouth, and of burning in the abdomen. Usually death ensues before a numbing effect on the intestine can be observed. After about an hour, there is severe vomiting. Pronounced motor weakness and cutaneous sensations similar to those above described soon follow. The pulse and respiration steadily fail until death occurs from asphyxia. The main causes of death are refractory ventricular arrhythmias and asystole and the overall in-hospital mortality is 5.5%.
The treatment is to empty the stomach by tube or by a non-depressant emetic. The physiological antidotes are atropine and digitalis or strophanthin, which should be injected subcutaneously in maximal doses. The historic antidotes of alcohol, strychnine, and warmth were employed, although with limited or no success.
The above description of poisoning is characteristic of an oral administration. However, poisoning may occur simply by picking the leaves without wearing gloves; the aconitine toxin is absorbed easily through the skin. From practical experience, the sap oozing from eleven picked leaves will cause cardiac symptoms for a couple of hours. In this event, there will be no gastrointestinal effects. Tingling will start at the point of absorption and extend up the arm to the shoulder, after which the heart will start to be affected.
Aconitase is an iron-containing enzyme catalyzing a reaction of significance in the tricarboxylic acid cycle: it is a key player in the central pathway of energy production, converting citrate in isocitrate.
Recent studies have demonstrated a very particular kind of inhibition by aconitine of aconitase of pig heart. The inhibition of aconitase activity by aconitine is totally non-competitive. The datum of inhibition constant indicates high affinity of aconitine by aconitase. The rate constant of inhibition and the half-life for aconitase
inhibition show high specific inhibition of the enzyme by the inhibitor. These results suggest a possible molecular reason for the toxic and pharmacological actions produced on experimental animals by aconitine.
Homeopathy uses many animal, plant, mineral, and synthetic substances in its remedies.
Homeopaths also use treatments called "nosodes" (from the Greek nosos, disease) made from diseased, pathological or poisonous products.
Also Aconitum is employed by homeopaths, but since aconitine is highly toxic, its use is not always recommended. Aconite's alkaloids have a narrow therapeutic index and the alkaloid type and amount vary with species, place of harvest, and adequacy of processing. Processing may reduce alkaloid content and/or alter alkaloid composition, thus reducing potency; however, poisoning may still occur after the consumption of processed aconite root.
In animal models, aconitine and related compounds have been shown to possess anti-inflammatory and analgesic properties. Studies using mechanical and thermal stimuli to cause pain in mice have shown that, at sub-analgesic doses, processed Aconitum root administered orally, both partially and dose-dependently inhibited the development of morphine tolerance in morphine-naive mice and reversed already developed morphine tolerance in morphine-tolerant mice when compared with placebo.
The following pharmacological effects of Aconitum alkaloid have been described on humans:
* Anti-inflammatory and anti-rheumatic activity
* Positive inotropic effects
* Regulation of neurological disorders
However, only limited studies are available, and most were performed in China and Japan.
• Aconitine was used to poison arrow heads or darts for the purposes of hunting, warfare or murder, expecially in China and Japan.
• "No, no, go not to Lethe, neither twist Wolf's bane, tight-rooted, for its poisonous wine Nor suffer thy pale forehead to be kissed By nightshade, ruby grape of Proserpine…”
Even the famous poet John Keats knew the effects and the relevances of medical herbs. In his poem “Ode on Melancholy” he mentions many kind of poisonous plants, such as Aconitum.
• Aconitum is well know from ancient times by farmers, because it caused the death of several cattles during pasturage.
• In 2004 Canadian actor Andre Noble died from aconitine poisoning. He accidentally ate some monkshood while he was on a hike with his aunt in Newfoundland.
In 2009 Lakhvir Singh of Feltham, west London, used aconitine to poison the food of her ex-lover (who died as a result of the poisoning) and his current fiancée. Singh received a life sentence for the murder)