Aconitine

Aconitine can interact with the voltage-dependent sodium-ion channels, which are proteins in the cell membranes of excitable tissues, such as cardiac and skeletal muscles and neurons. These proteins are highly selective for sodium ions. They open very quickly to depolarize the cell membrane potential, causing the upstroke of an action potential. Normally, the sodium channels close very rapidly, but the depolarization of the membrane potential causes the opening (activation) of potassium channels and potassium efflux, which results in repolarization of the membrane potential.

Aconitine binds to the channel at the neurotoxin binding site 2 on the alpha subunit (the same site bound by batrachotoxin, veratridine, and grayanotoxin).^[9] This binding results in a sodium-ion channel that stays open longer. Aconitine suppresses the conformational change in the sodium-ion channel from the active state to the inactive state. The membrane stays depolarized due to the constant sodium influx (which is 10–1000-fold greater than the potassium efflux). As a result, the membrane cannot be repolarized. The binding of aconitine to the channel also leads to the channel to change conformation from the inactive state to the active state at a more negative voltage.^[10] In neurons, aconitine increases the permeability of the membrane for sodium ions, resulting in a huge sodium influx in the axon terminal. As a result, the membrane depolarizes rapidly. Due to the strong depolarization, the permeability of the membrane for potassium ions increases rapidly, resulting in a potassium reflux to release the positive charge out of the cell. Not only the permeability for potassium ions but also the permeability for calcium ions increases as a result of the depolarization of the membrane. A calcium influx takes place. The increase of the calcium concentration in the cell stimulates the release of the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine binds to acetylcholine receptors at the postsynaptic membrane to open the sodium-channels there, generating a new action potential.

Research with mouse nerve-hemidiaphragm muscle preparation indicate that at low concentrations (<0.1 μM) aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension.^[11] Action potentials are generated more often at this concentration. At higher concentration (0.3–3 μM) aconitine decreases the electrically evoked acetylcholine release, resulting in a decrease in muscle tension. At high concentration (0.3–3 μM), the sodium-ion channels are constantly activated, transmission of action potentials is suppressed, leading to non-excitable target cells or paralysis.

Biosynthesis and total synthesis of related alkaloids

Aconitine is biosynthesized by the

Likewise, only a few alkaloids of the aconitine family have been synthesized in the laboratory. In particular, despite over one hundred years having elapsed since its isolation, the prototypical member of its family of norditerpenoid alkaloids, aconitine itself, represents a rare example of a well-known natural product that has yet to succumb to efforts towards its total synthesis. The challenge that aconitine poses to synthetic organic chemists is due to both the intricate interlocking hexacyclic ring system that makes up its core and the elaborate collection of oxygenated functional groups at its periphery. A handful of simpler members of the aconitine alkaloids, however, have been prepared synthetically. In 1971, the Weisner group discovered the total synthesis of talatisamine (a C19-norditerpenoid).^[14] In the subsequent years, they also discovered the total syntheses of other C19-norditerpenoids, such as chasmanine,^[15] and 13-deoxydelphonine.^[16]

The total synthesis of napelline (Scheme a) begins with aldehyde 100.^[14] In a 7 step process, the A-ring of napelline is formed (104). It takes another 10 steps to form the lactone ring in the pentacyclic structure of napelline (106). An additional 9 steps creates the enone-aldehyde 107. Heating in methanol with potassium hydroxide causes an aldol condensation to close the sixth and final ring in napelline (14). Oxidation then gives rise to diketone 108 which was converted to (±)-napelline (14) in 10 steps.

A similar process is demonstrated in Wiesner's synthesis of 13-desoxydelphinone (Scheme c).

Lastly, talatisamine (Scheme d) is synthesized from diene 116 and nitrile 117.

More recently, the laboratory of the late David Y. Gin completed the total syntheses of the aconitine alkaloids nominine[17] and neofinaconitine.^[18]

Metabolism

Aconitine is metabolized by cytochrome P450 isozymes (CYPs). There has been research in 2011 in China to investigate in-depth the CYPs involved in aconitine metabolism in human liver microsomes.^[19] It has been estimated that more than 90 percent of currently available human drug metabolism can be attributed to eight main enzymes (CYP 1A2, 2C9, 2C8, 2C19, 2D6, 2E1, 3A4, 3A5).^[20] The researchers used recombinants of these eight different CYPs and incubated it with aconitine. To initiate the metabolism pathway the presence of NADPH was needed. Six CYP-mediated metabolites (M1–M6) were found by liquid chromatography, these six metabolites were characterized by mass-spectrometry. The six metabolites and the involved enzymes are summarized in the following table:

Selective inhibitors were used to determine the involved CYPs in the aconitine metabolism. The results indicate that aconitine was mainly metabolized by CYP3A4, 3A5 and 2D6. CYP2C8 and 2C9 had a minor role to the aconitine metabolism, whereas CYP1A2, 2E1 and 2C19 did not produce any aconitine metabolites at all. The proposed metabolic pathways of aconitine in human liver microsomes and the CYPs involved to it are summarized in the table above.

Uses

Aconitine was previously used as an antipyretic and analgesic and still has some limited application in herbal medicine, although the narrow therapeutic index makes calculating appropriate dosage difficult.^[21] Aconitine is also present in Yunnan Baiyao, a proprietary traditional Chinese medicine.^[22]

Toxicity

Consuming as little as 2

• Neurological:
  perioral
  area and four limbs; muscle weakness in four limbs
• Cardiovascular: hypotension, palpitations, chest pain, bradycardia, sinus tachycardia, ventricular ectopics and other arrhythmias, ventricular arrhythmias, and junctional rhythm
• Gastrointestinal: nausea, vomiting, abdominal pain, and diarrhea
• Others: dizziness,
  lacrimation

Progression of symptoms: the first symptoms of aconitine poisoning appear approximately 20 minutes to 2 hours after oral intake and include paresthesia, sweating and nausea. This leads to severe vomiting, colicky diarrhea, intense pain and then paralysis of the skeletal muscles. Following the onset of life-threatening arrhythmia, including ventricular tachycardia and ventricular fibrillation, death finally occurs as a result of respiratory paralysis or cardiac arrest.^[25]

During the Indian Rebellion of 1857, a British detachment was the target of attempted poisoning with aconitine by the Indian regimental cooks. The plot was thwarted by John Nicholson who, having detected the plot, interrupted the British officers just as they were about to consume the poisoned meal. The chefs refused to taste their own preparation, whereupon it was force-fed to a monkey who "expired on the spot". The cooks were hanged.

Aconitine was the poison used by George Henry Lamson in 1881 to murder his brother-in-law in order to secure an inheritance. Lamson had learned about aconitine as a medical student from professor Robert Christison, who had taught that it was undetectable—but forensic science had improved since Lamson's student days.^[30][31][32]

Rufus T. Bush, American industrialist and yachtsman, died on September 15, 1890, after accidentally taking a fatal dose of aconite.

In 1953 aconitine was used by a Soviet biochemist and poison developer, Grigory Mairanovsky, in experiments with prisoners in the secret NKVD laboratory in Moscow. He admitted killing around 10 people using the poison.^[33]

In 2004 Canadian actor

In 2009

In 2022, twelve diners at a restaurant in York Region became acutely ill following a meal. All twelve became seriously ill and four of them were admitted to the intensive care unit after the suspected poisoning.^[35]

In popular culture

Aconitine was a favorite poison in the ancient world. The poet Ovid, referring to the proverbial dislike of stepmothers for their step-children, writes:

Lurida terribiles miscent aconita novercae.^[36]

Fearsome stepmothers mix lurid aconites.

Aconitine was also made famous by its use in

In the third season of the Netflix series You, two of the main characters poison each other with Aconite. One survives (due to a lower dose and an antidote), and the other is killed.

Hannah McKay (Yvonne Strahovski), a serial killer in the Showtime series Dexter uses Aconite on at least three occasions to poison her victims.

In season two episode sixteen of the series Person Of Interest aconitine is shown in a syringe stuck to the character Shaw (Sarah Shahi) nearly being injected and causing her death, until she is rescued by Reese (Jim Caviezel)

In a 2017 episode of The Doctor Blake Mysteries, fight manager Gus Jansons (Steve Adams) murdered his boxer, Mickey Ellis (Trey Coward), during a match by applying aconitine he had put in petroleum jelly and applying it to a cut over the boxer’s eye. He feared being blackmailed over a murder he helped cover up. He had made the poison from wolfsbane he had seen in a local garden.^[38]

See also

• Pseudaconitine

References