Taxine alkaloids

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]

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 ${\displaystyle {\ce {C37H52NO10}}}$.[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]

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.[6][22][4] 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.[23] Taxines are also absorbed efficiently via the skin and Taxus species should thus be handled with care and preferably with gloves.[24] Taxus Baccata leaves contain approximately 5 mg of Taxines per 1g of leaves.[22] The estimated lethal dose (LD_min) of Taxus baccata leaves is 3.0-6.5 mg/kg body weight for humans[25] There is currently no known antidotes for yew poisoning, but drugs such as atropine have been used to treat the symptoms.[26] 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,[27] fallen leaves are also toxic.[28] Although poisoning usually occurs when leaves of yew trees are eaten, in at least one case a victim inhaled sawdust from a yew tree.[29] One major reason as to why different studies show different LD results is that it is difficult to measure Taxine alkaloids accurately.[30]

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.[31]

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.

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).[37]

There have been many studies about the toxicity of the taxine alkaloids[38][39] 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.[40] 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.[41]

Some taxine alkaloids have been isolated to study its effects and characteristics, this has allowed the discovery of some of the particular effects of each substance of the plant, for example: taxine A does not influence blood pressure, taxol causes cardiac disturbances in some people, and that taxine B is the most toxic of these substances.[42]

Because a derivative from the yew, paclitaxel, functions as an anticancer drug, there have been investigations to show whether taxine B could also be used as a pharmacodrug.[43]

• Taxane
• Taxadiene
• Omacetaxine

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