Taxine alkaloids

Taxine alkaloids, which are often named under the collective title of taxines, are the toxic chemicals that can be isolated from the yew tree.[2][3] The amount of taxine alkaloids depend on the species of yew with Taxus baccata and Taxus cuspidata containing the most.[4] The major taxine alkaloids are taxine A and taxine B although there are at least 10 different alkaloids.[5] Until 1956, it was believed that all the taxine alkaloids were one single compound named taxine.[4]

Taxine A

Taxine A
Names
IUPAC name
2α,13α-Diacetoxy-7β,10β-dihydroxy-9-oxo-2(3→20)-abeotaxa-4(20),11-dien-5α-yl (2R,3S)-3-(dimethylamino)-2-hydroxy-3-phenylpropanoate
Other names
(1R,2S,3E,5S,7S,8S,10R,13S)-2,13-Diacetoxy-7,10-dihydroxy-8,12,15,15-tetramethyl-9-oxotricyclo[9.3.1.14,8]hexadeca-3,11-dien-5-yl (2R,3S)-3-(dimethylamino)-2-hydroxy-3-phenylpropanoate
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
UNII
Properties
C35H47NO10
Molar mass 641.751 g·mol−1
Melting point 204-206 °C[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Taxine B

Taxine B
Names
IUPAC name
10β-Acetoxy-1,2α,9α-trihydroxy-13-oxotaxa-4(20),11-dien-5α-yl (3R)-3-(dimethylamino)-3-phenylpropanoate
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
Properties
C33H45NO8
Molar mass 583.722 g·mol−1
Melting point 115 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

The taxine alkaloids are cardiotoxins with taxine B being the most active.[6] Taxine alkaloids have no medical uses but Paclitaxel and other taxanes that can be isolated from yews have been used as chemotherapy drugs.[7]

Provenance
Taxus baccata's tree and its aril

Taxine can be found in Taxus species: Taxus cuspidata, T. baccata (English yew), Taxus x media, Taxus canadensis, Taxus floridana and Taxus brevifolia (Pacific or western yew). All of these species contain taxine in every part of the plant except in the aril, the fleshy covering of the seeds (berries). Each species contains a different amount of taxine concentration, which leads to varying toxicities within the genus. This is the case of the Taxus brevifolia or Pacific yew and the Taxus baccata (English yew); T. baccata contains high taxine concentration, which leads to a high toxicity, whereas T. brevifolia has a low toxicity. There are seasonal changes in the concentrations of taxine in yew plants, with the highest concentrations during the winter, and the lowest in the summer.[8] Taxus species are one of the few trees whose poison is not denatured upon death; in other words, the effect of the Taxine continues functioning independently of the life of the yew in which it is contained.[9]

These species have distinctive leaves, which are needle-like, small, spirally arranged but twisted so they are two-ranked, linear-lanceolate. They are also characterized by their ability to regenerate from stumps and roots.[8] They are found all over Europe and live in conditions similar to the oceanic specia and better in mixed forests (coniferous), on limestone substrates, and occupy rock cliffs and slopes. They are sensitive to low temperatures, the reason why they cannot be found in Northern Scandinavia.[10]

History

The toxic nature of yew trees has been known for millennia.[11] There are a number of early recorded examples of poisonings by Greek and Roman writers including Julius Caesar’s account of Cativolcus, king of Eburones, who committed suicide using the “juice of the yew”.[12] The first attempt to extract the poisonous substance in the yew tree was in 1828 by Piero Peretti who isolated a bitter substance.[13] In 1856, H. Lucas, a pharmacist in Arnstadt, prepared a white, alkaloid powder from the foliage of Taxus baccata L. which he named taxine.[14] The crystalline form of the substance was isolated in 1876 by W. Marmé, a French chemist. A. Hilger and F. Brande used elemental combustion analysis in 1890 to suggest the first molecular formula of .[4]

For the next 60 years, it was generally accepted that taxine was made of a single compound and it was well known enough for Agatha Christie to use it as a poison in A Pocket Full of Rye (1953). However, in 1956, Graf and Boeddeker discovered that Taxine was actually a complex mixture of alkaloids rather than a single alkaloid.[15] Using electrophoresis, they were able to isolate the two major components, Taxine A and Taxine B. Taxine A was the fastest moving band and accounted for 1.3% of the alkaloid mixture and Taxine B was the slowest moving band and accounted for 30% of the mixture.[16] The full structure of Taxine A was reported in 1982[1] and of Taxine B in 1991.[17]

Toxicity in humans
Taxus baccata's seeds
3,5-Dimethoxyphenol molecule, used in the Taxine poisoning diagnosis
The structure of Taxine B, the cardiotoxic chemical in the yew plant

The entire yew bush, except the aril (the red flesh of the berry covering the seed), is toxic due to a group of chemicals called Taxine alkaloids. Their cardiotoxicity is well known and act via calcium and sodium channel antagonism, causing an increase in cytoplasmic calcium currents of the myocardial cells. The seeds contains the highest concentrations of these alkaloids.[18][19] If any leaves or seeds of the plant are ingested, urgent medical advice is recommended as well as observation for at least 6 hours after the point of ingestion.[20][21] The most cardiotoxic Taxine is Taxine B followed by Taxine A - Taxine B also happens to be the most common alkaloid in the Taxus species.[22][23][24] The Taxine alkaloids are absorbed quickly from the intestine and in high enough quantities can cause death due to general cardiac failure, cardiac arrest or respiratory failure.[25] Taxines are also absorbed efficiently via the skin and Taxus species should thus be handled with care and preferably with gloves.[26] Taxus Baccata leaves contain approximately 5mg of Taxines per 1g of leaves.[27] The estimated lethal dose (LDmin) of Taxus baccata leaves is 3.0-6.5 mg/kg body weight for humans[28] There is currently no known antidotes for yew poisoning, but drugs such as atropine have been used to treat the symptoms.[29] Taxine remains in the plant all year, with maximal concentrations appearing during the winter. Dried yew plant material retains its toxicity for several months and even increases its toxicity as the water is removed[30], fallen leaves are also toxic[31]. Although poisoning usually occurs when leaves of yew trees are eaten, in at least one case a victim inhaled sawdust from a yew tree.[32] One major reason as to why different studies show different LD results is that it is difficult to measure Taxine alkaloids accurately.[33]

Male and monoecious yews in this genus release toxic pollen, which can cause the mild symptoms of Taxine poisoning. The pollen are also a trigger for asthma. These pollen grains are only 15 microns in size, and can easily pass through most window screens.[34]

Clinical signs

Cardiac and cardiovascular effects:

Arrhythmia, irregular heartbeats leading to lower cardiac output - in itself is a very severe symptom, especially ventricular arrytmias can lead to circulatory collapse(via cardiac arrest) very fast if not treated

Bradycardia, fewer heart beats per time unit.

Both these effects lead to:

Hypotension which gives many symptoms such as:

and many other typical signs of low blood pressure


Intestinal effects:


Respiratory effects:

  • Respiratory distress(shortness of breath)


If the poisoning is severe and not treated:

  • Loss of consciousness - lack of oxygen due to low blood pressure and respiratory distress forces the body to shut down all but the most vital functions.
  • Respiratory failure, breathing stops
  • Circulatory collapse, the blood pressure drops to the point that not even the most basic functions can be sustained

[35][36][37]

Diagnosis

The diagnosis of yew poisoning is very important if the patient is not already aware of having ingested parts of the yew tree. The method of diagnosis is the determination of 3,5-dimethoxyphenol, a product of the hydrolysis of the glycosidic bond in taxine, in the blood, the gastric contents, the urine and the tissues of the patient. This analysis can be done by gas or liquid chromatography and also by mass spectroscopy.

Treatment

There are no specific antidotes for taxine, so patients can only receive treatment for their symptoms.

It is also important to control the blood pressure and the heart rate to treat the heart problems. Atropine has been used successfully in humans to treat bradycardias and arrhythmias caused by taxine. It is more effective if administrated early, but it is also necessary to be cautious with the administration because it can produce an increase in myocardial oxygen demand and potentiate myocardial hypoxia and dysfunction. An artificial cardiac pacemaker can also be installed to control the heartbeat.

Other treatments are useful to treat the other symptoms of poisoning: positive pressure ventilation if respiratory distress is present; fluid therapy to support blood pressure and maintain hydration and renal function; gastrointestinal protectants; and it may also be necessary to control aggressive behaviour and convulsions with tranquilizers.[38]

Prevention

The toxic effects of T. baccata have been known since ancient times. In most cases, poisoning is accidental, especially in cases involving children or animals. However, there are cases in which the poison is used as a suicide method.[39]

Because taxine poisoning is often only diagnosed after the death of the patient due to its rapid effect, preventing exposure is very important. Even dried parts of the plant are toxic because they still contain taxine molecules. Pet owners must ensure that yew branches or leaves are not used as toys for dogs or as perches for domestic birds.

Toxicity in animals

The effects of Taxine in humans are very similar to the effects on animals. It has the same mechanisms of action, and most of the times the ingestion of yew material is diagnosed with the death of the animal. Moreover, clinical signs, diagnosis, treatment and prevention are mostly the same as in humans. This was seen due to the many experiments realized on rats, pigs, and other animals.[8]

However, there are some animals that are immune to the effects of taxine such macaws and white-tail deer.

Mechanism of action

The toxicity of the yew plant is due to some substances that are found in it, the principal ones are: toxic alkaloids (taxine B, paclitaxel, isotaxine B, taxine A), glycosides (taxicatine) and taxane derivates (taxol A, taxol B).[40]

There have been a lot of studies about the toxicity of the taxine alkaloids[41][42] and they have shown that their mechanism of action is interfering with the sodium and calcium channels of the myocardial cells, increasing the cytoplasmic calcium concentrations. Their mechanism is similar to drugs such as verapamil, although taxines are more cardioselective.[43] They also reduce the rate of the depolarization of the action potential in a dose-dependent manner. This produces bradycardia, hypotension, depressed myocardial contractility, conduction delay, arrhythmias, and other complications.[44]

Some taxine alkaloids have been isolated to study its effects and characteristics, this has allowed us to discover some of the particular effects of each substance of the plant, for example: it showed that taxine A doesn’t influence in blood pressure, that taxol causes itself cardiac disturbances in some patients, and that taxine B is the most toxic substance.[45]

There has been a recent discovery in a molecule derived from the yew: paclitaxel. It has been proved that it functions as an anticancer drug; because of it there have been some investigations to show whether taxine B could also be used as a pharmacodrug, but it hasn’t been proved as such yet.[46]

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gollark: Bonds are just a promise by some organization to pay back your money + interest in some amount of time.
gollark: If the company implodes or something you can lose the value of your shares, but not more because limited liability.
gollark: Shares are just partial ownership in a company - you get that amount of their profits and that amount of control of it (by voting for the board of directors).
gollark: Though it's shares, not bonds. They're different.

See also

References
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  2. Veterinary toxicology : basic and clinical principles. Gupta, Ramesh C. (Ramesh Chandra), 1949- (2nd ed.). Oxford: Academic. 2012. ISBN 9780123859266. OCLC 778786624.CS1 maint: others (link)
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Further reading

Asheesh K. Tiwary, Birgit Puschner, Hailu Kinde, Elizabeth R. Tor (2005). "Diagnosis of Taxus (Yew) poisoning in a horse". Journal of Veterinary Diagnostic Investigation.

Andrea Persico, Giuseppe Bacis, Francesca Uberti, Claudia Panzeri, Chiara Di Lorenzo, Enzo Moro, and Patrizia Restani (2011). "Identification of Taxine Derivatives in Biological Fluids from a Patient after Attempted Suicide by Ingestion of Yew (Taxus baccata) Leaves". Journal of Analytical Toxicology. Vol. 35

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